Ureas having androgen receptor degradation activity and uses thereof

ABSTRACT

The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of cancer and related diseases and conditions. In some embodiments, the compounds disclosed herein exhibit androgen receptor degradation activity.

This application is a continuation of U.S. application Ser. No.17/028,612, filed Sep. 22, 2020, which claims the benefit of priority toU.S. Provisional Application No. 62/903,997, filed Sep. 23, 2019, whichare both hereby incorporated by reference in their entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to novel compounds, pharmaceuticalcompositions containing such compounds, and their use in prevention andtreatment of diseases and conditions, e.g., cancer. The compoundsdisclosed herein exhibit androgen receptor degradation activity.

BACKGROUND OF THE DISCLOSURE

Androgens, through binding to the Androgen Receptor (AR), govern a widerange of physiological processes. For example, androgens are requiredfor normal prostate development and function as they are key in the ARsignaling pathway. Unfortunately, the AR signaling pathway is alsoimplicated in the development and survival of cancers, such as prostate,breast, and other cancers (see, e.g., “Androgen Receptor in ProstateCancer”, Endocrine Reviews, 2004, 25(2), 276-308; and “Androgenreceptors beyond prostate cancer: ann old marker as a new target”,Oncotarget, 2014, 6(2), 592-603).

Traditional methods to treat cancers where AR is implicated, such asprostate cancer, involves AR signaling suppression through, for example,androgen deprivation therapy. Such therapy includes chemical and/orsurgical castration. Alternatively, anti-androgen therapy may bepursued, whereby a patient is treated with an AR inhibitor, such asenzalutamide (XTANDI®). Although these treatment methods have resultedin improved prognoses for individuals with androgen receptor positivecancer, cancer progression is eventually observed and occurs through,for example, AR gene amplification and/or development of AR mutations.

Accordingly, there exists a need to treat AR positive cancer that haltsprogression of the cancer, even if the individual has experienced one ormore prior therapies. One approach to achieve this goal would be toutilize the naturally occurring cellular ubiquitin-mediated degradation.Without being bound to any theory, it is believed that AR degradationmay occur when both AR and a ubiquitin ligase are bound and brought intoclose proximity.

Cereblon (“CRBN”) E3 ubiquitin ligase is a ubiquitin ligase that formsan E3 ubiquitin ligase complex with damaged DNA binding protein 1 andCullin 4. It functions as a substrate receptor by bringing thesubstrates to close proximity for ubiquitination and subsequentdegradation by proteasomes. Recently, it has been discovered that smallmolecules drugs, e.g., thalidomide and its close analogs, lenalidomideand pomalidomide, can simultaneously interact with CRBN and some otherproteins. In doing so, CRBN may be exploited for target proteindegradation, such as IKZF1 and IKZF3. This is thought to account for theanti-myeloma effects of thalidomide and related compounds.

Thus, disclosed herein are compounds useful for the treatment ofcancers, such as prostate cancer. In some instances, the cancer is ARpositive. The compounds disclosed herein are bifunctional molecules,where one portion of the molecule is capable of interacting with CRBNand the other portion, which is linked to the CRBN-interacting portionof the molecule via a linking moiety, is capable of interacting with AR.

SUMMARY OF THE DISCLOSURE

In some embodiments, the present disclosure is directed to a compound ofFormula (1), or a pharmaceutically acceptable salt thereof:

wherein:

X₁ is CR₁ or N;

X₂ is CR₂ or N;

X₃ is CR₃ or N;

X₄ is CR₄ or N;

each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkyl, each of which is substitutedwith 0, 1, 2, or 3 R_(S);

each R₅ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₆ is independently selected from hydrogen, C₁-C₃alkyl, andC₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3 R_(S);

each R₇ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₈ is independently selected from hydrogen, hydroxyl, C₁-C₃alkyl,and C₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3R_(S), or two R₈ groups are taken together to form an oxo;

each R₉ is independently selected from hydrogen, C₁-C₃alkyl,—C(═O)—(C₁-C₃alkyl), —C(═O)—O—(C₁-C₃alkyl), and —C(═O)—NH—(C₁-C₃alkyl),each of which is substituted with 0, 1, 2, or 3 R_(S), or two R₉ groupsare taken together to form a 3- to 6-membered heterocycle or heteroaryl;

each R_(S) is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN;

L is a linker of 1 to 16 carbon atoms in length, wherein one or morecarbon atoms are optionally replaced by C(═O), O, N(R₉), S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein theR₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are eachindependently substituted with 0, 1, 2, or 3 R_(S);

m is 0, 1, 2, or 3; and

n is 0, 1, 2, or 3,

wherein each hydrogen atom is independently and optionally replaced by adeuterium atom.

In some embodiments, the compound of Formula (1) may be a compound ofFormula (1A)

In some embodiments, the present disclosure is directed to a compound ofFormula (2), or a pharmaceutically acceptable salt thereof:

wherein:

X₁ is CR₁ or N;

X₂ is CR₂ or N;

X₃ is CR₃ or N;

X₄ is CR₄ or N;

each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkyl, each of which is substitutedwith 0, 1, 2, or 3 R_(S);

each R₅ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₆ is independently selected from hydrogen, C₁-C₃alkyl, andC₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3 R_(S);

each R₇ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₈ is independently selected from hydrogen, hydroxyl, C₁-C₃alkyl,and C₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3R_(S), or two R₈ groups are taken together to form an oxo;

each R₉ is independently selected from hydrogen, C₁-C₃alkyl,—C(═O)—(C₁-C₃alkyl), —C(═O)—O—(C₁-C₃alkyl), and —C(═O)—NH—(C₁-C₃alkyl),each of which is substituted with 0, 1, 2, or 3 R_(S), or two R₉ groupsare taken together to form a 3- to 6-membered heterocycle or heteroaryl;

each R_(S) is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN;

L is a linker of 1 to 16 carbon atoms in length, wherein one or morecarbon atoms are optionally replaced by C(O), O, N(R₉), S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein theR₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are eachindependently substituted with 0, 1, 2, or 3 R_(S);

m is 0, 1, or 2;

n is 0, 1, 2, or 3; and

o is 0, 1, 2, or 3,

wherein each hydrogen atom is independently and optionally replaced by adeuterium atom.

In some embodiments, the compound of Formula (2) may be a compound ofFormula (2A)

In some embodiments, the

group may be selected from

In some embodiments, the

group may be selected from

In some embodiments, the

group may be selected from

In some embodiments, L may be selected from:

Also disclosed herein is a method of treating cancer, in a subject inneed thereof, comprising administering to said subject a compound ofFormula (1) (e.g. Formula (1A)) or (2) (e.g. Formula (2A)), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of Formula (1) or (2) or apharmaceutically acceptable salt thereof. In at least one embodiment,the pharmaceutical composition of the present disclosure may be for usein (or in the manufacture of medicaments for) the treatment of cancer inthe subject in need thereof.

In at least one embodiment, a therapeutically-effective amount of apharmaceutical composition of the present disclosure may be administeredto a subject diagnosed with cancer. In some embodiments, the cancer isselected from prostate cancer, head and neck cancer, skin cancer,sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer,lung cancer, gastric carcinoma, esophageal carcinoma, pancreaticadenocarcinoma, colorectal cancer, connective tissue cancer,glioblastoma multiforme, cervical cancer, uterine cancer, ovariancancer, and breast cancer.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate the disclosed embodiments and,together with the description, explain the principles of the disclosedembodiments. In the drawings:

FIG. 1 illustrates the androgen receptor (AR) degradative activity ofcompounds 1-27, 1-49, 2-8, and 2-10 in LNCAP cell lines 24 hours afteradministration using Western blot analysis.

DETAILED DESCRIPTION OF THE DISCLOSURE Definitions

As used herein, “cancer” refers to diseases, disorders, and conditionsthat involve abnormal cell growth with the potential to invade or spreadto other parts of the body. Exemplary cancers include, but are notlimited to, prostate cancer, head and neck cancer, skin cancer, sarcoma,renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lungcancer, gastric carcinoma, esophageal carcinoma, pancreaticadenocarcinoma, colorectal cancer, connective tissue cancer,glioblastoma multiforme, cervical cancer, uterine cancer, ovariancancer, and breast cancer.

As used herein, the term “androgen receptor positive” means thatandrogen receptor is detected by one or more analytical methods, e.g.,immunohistochemistry. For example, analysis of a biopsy of a subject'stumor may indicate the presence of androgen receptor. AR status may betested by circulating cancer cells or circulating tumor DNA in a bloodtest. In some circumstances an AR test may not be performed.

“Subject” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation, or experiment. The methodsdescribed herein may be useful for both human therapy and veterinaryapplications. In one embodiment, the subject is a human.

As used herein, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient. In yet another embodiment, “treatment” or“treating” refers to inhibiting the progression of a disease ordisorder, either physically, e.g., stabilization of a discerniblesymptom, physiologically, e.g., stabilization of a physical parameter,or both. In yet another embodiment, “treatment” or “treating” refers todelaying the onset of a disease or disorder.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CN isattached through the carbon atom.

By “optional” or “optionally” it is meant that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which is does not. It will be understood by thoseskilled in the art, with respect to any group containing one or moresubstituents, that such groups are not intended to introduce anysubstitution or substitution patterns that are sterically impractical,synthetically non-feasible and/or inherently unstable.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example, “C₁-C₆ alkyl” is intendedto encompass C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “alkenyl” as used herein refers to an unsaturated, two-carbongroup having a carbon-carbon double bond, referred to herein asC₂-alkenyl.

The term “alkoxy” as used herein refers to an alkyl or cycloalkylcovalently bonded to an oxygen atom.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-8 carbonatoms, referred to herein as (C₁-C₈)alkyl. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, andoctyl. In some embodiments, “alkyl” is a straight-chain hydrocarbon. Insome embodiments, “alkyl” is a branched hydrocarbon.

The term “alkynyl” as used herein refers to an unsaturated, two-carbongroup having a carbon-carbon triple bond, referred to herein asC₂-alkynyl.

The term “aryl” as used herein refers to a mono-, bi-, or othermulti-carbocyclic, aromatic ring system with 5 to 14 ring atoms. Thearyl group can optionally be fused to one or more rings selected fromaryls, cycloalkyls, heteroaryls, and heterocyclyls. The aryl groups ofthis present disclosure can be substituted with groups selected fromalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.Exemplary aryl groups include, but are not limited to, phenyl, tolyl,anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well asbenzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.Exemplary aryl groups also include but are not limited to a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “C₆-aryl.”

The term “cycloalkyl” as used herein refers to a saturated orunsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of3-16 carbons, or 3-8 carbons, referred to herein as “(C₃-C₈)cycloalkyl,”derived from a cycloalkane. Exemplary cycloalkyl groups include, but arenot limited to, cyclohexanes, cyclohexenes, cyclopentanes, andcyclopentenes. Cycloalkyl groups may be substituted with alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Cycloalkyl groups can be fused to other cycloalkyl (saturated orpartially unsaturated), aryl, or heterocyclyl groups, to form a bicycle,tetracycle, etc. The term “cycloalkyl” also includes bridged andspiro-fused cyclic structures which may or may not contain heteroatoms.

The terms “halo” or “halogen” as used herein refer to —F, —Cl, —Br,and/or —I.

The term “haloalkyl group” as used herein refers to an alkyl groupsubstituted with one or more halogen atoms.

The term “heteroaryl” as used herein refers to a mono-, bi-, ormulti-cyclic, aromatic ring system containing one or more heteroatoms,for example 1-4 heteroatoms, such as nitrogen, oxygen, and sulfur.Heteroaryls can be substituted with one or more substituents includingalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Heteroaryls can also be fused to non-aromatic rings. Illustrativeexamples of heteroaryl groups include, but are not limited to,pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl,pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl,pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl,phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include,but are not limited to, a monocyclic aromatic ring, wherein the ringcomprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as“(C₂-C₅)heteroaryl.” In some embodiments, a heteraryl contains 5 to 10ring atoms, 1 to 4 of which are heteroatoms selected from N, O, and S.In some embodiments, a heteroaryl contains 5 to 8 ring atoms, 1 to 4 ofwhich are heteroatoms selected from N, O, and S.

The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as usedherein each refer to a saturated or unsaturated 3- to 18-membered ringcontaining one, two, three, or four heteroatoms independently selectedfrom nitrogen, oxygen, phosphorus, and sulfur. Heterocycles can bearomatic (heteroaryls) or non-aromatic. Heterocycles can be substitutedwith one or more substituents including alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide and thioketone. Heterocycles alsoinclude bicyclic, tricyclic, and tetracyclic groups in which any of theabove heterocyclic rings is fused to one or two rings independentlyselected from aryls, cycloalkyls, and heterocycles. Exemplaryheterocycles include acridinyl, benzimidazolyl, benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl,dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl,dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl,imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl,isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl,oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl,pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl,pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl,quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl,thienyl, thiomorpholinyl, thiopyranyl, and triazolyl. In someembodiments, a heterocycle contains 5 to 10 ring atoms, 1 to 4 of whichare heteroatoms selected from N, O, and S. In some embodiments, aheterocycle contains 5 to 8 ring atoms, 1 to 4 of which are heteroatomsselected from N, O, and S.

The terms “hydroxy” and “hydroxyl” as used herein refer to —OH.

The term “oxo” as used herein refers to a double bond to an oxygen atom(i.e., ═O). For example, when two geminal groups on a carbon atom are“taken together to form an oxo”, then a carbonyl (i.e., C═O) is formed.

The term “pharmaceutically acceptable carrier” as used herein refers toany and all solvents, dispersion media, coatings, isotonic andabsorption delaying agents, and the like, that are compatible withpharmaceutical administration. The use of such media and agents forpharmaceutically active substances is well known in the art. Thecompositions may also contain other active compounds providingsupplemental, additional, or enhanced therapeutic functions.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt form of a compound of this disclosure wherein the salt is nontoxic.Pharmaceutically acceptable salts of the compounds of this disclosureinclude those derived from suitable inorganic and organic acids andbases. A “free base” form of a compound, for example, does not containan ionically bonded salt.

The phrase “and pharmaceutically acceptable salts and deuteratedderivatives thereof” is used interchangeably with “and pharmaceuticallyacceptable salts thereof and deuterated derivatives of any of theforgoing” in reference to one or more compounds or formulae of thedisclosure. These phrases are intended to encompass pharmaceuticallyacceptable salts of any one of the referenced compounds, deuteratedderivatives of any one of the referenced compounds, and pharmaceuticallyacceptable salts of those deuterated derivatives.

One of ordinary skill in the art would recognize that, when an amount of“a compound or a pharmaceutically acceptable salt thereof” is disclosed,the amount of the pharmaceutically acceptable salt form of the compoundis the amount equivalent to the concentration of the free base of thecompound. It is noted that the disclosed amounts of the compounds ortheir pharmaceutically acceptable salts thereof herein are based upontheir free base form.

Suitable pharmaceutically acceptable salts are, for example, thosedisclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66,1-19. For example, Table 1 of that article provides the followingpharmaceutically acceptable salts:

TABLE 1 Acetate Iodide Benzathine Benzenesulfonate IsethionateChloroprocaine Benzoate Lactate Choline Bicarbonate LactobionateDiethanolamine Bitartrate Malate Ethylenediamine Bromide MaleateMeglumine Calcium edetate Mandelate Procaine Camsylate Mesylate AluminumCarbonate Methylbromide Calcium Chloride Methylnitrate Lithium AcetateIodide Benzathine Citrate Methylsulfate Magnesium Dihydrochloride MucatePotassium Edetate Napsylate Sodium Edisylate Nitrate Zinc EstolatePamoate (Embonate) Esylate Pantothenate Fumarate Phosphate/diphosphateGluceptate Polygalacturonate Gluconate Salicylate Glutamate StearateGlycollylarsanilate Subacetate Hexylresorcinate Succinate HydrabamineSulfate Hydrobromide Tannate Hydrochloride Tartrate HydroxynaphthoateTeociate Triethiodide

Non-limiting examples of pharmaceutically acceptable acid addition saltsinclude: salts formed with inorganic acids, such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid;salts formed with organic acids, such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acid;and salts formed by using other methods used in the art, such as ionexchange. Non-limiting examples of pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium, and N⁺(C₁₋₄ alkyl)₄ salts.This disclosure also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Suitablenon-limiting examples of alkali and alkaline earth metal salts includesodium, lithium, potassium, calcium, and magnesium. Further non-limitingexamples of pharmaceutically acceptable salts include ammonium,quaternary ammonium, and amine cations formed using counterions such ashalide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and aryl sulfonate. Other suitable, non-limiting examples ofpharmaceutically acceptable salts include besylate and glucosaminesalts.

As used herein, nomenclature for compounds including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. One of skill in the art can readily ascertain thestructure of a compound if given a name, either by systemic reduction ofcompound structure using naming conventions, or by commerciallyavailable software, such as CHEMDRAW™ (Cambridgesoft Corporation,U.S.A.).

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “5,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present disclosure encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly. In some embodiments, an enantiomer orstereoisomer may be provided substantially free of the correspondingenantiomer.

In some embodiments, the compound is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, thecompound mixture has an (S)-enantiomeric excess of greater than about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about99.5%, or more. In other embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5%, or more. In otherembodiments, the compound mixture has an (R)-enantiomeric purity ofgreater than about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, about 99%, about 99.5% or more. In some other embodiments, thecompound mixture has an (R)-enantiomeric excess of greater than about55% to about 99.5%, greater than about 60% to about 99.5%, greater thanabout 65% to about 99.5%, greater than about 70% to about 99.5%, greaterthan about 75% to about 99.5%, greater than about 80% to about 99.5%,greater than about 85% to about 99.5%, greater than about 90% to about99.5%, greater than about 95% to about 99.5%, greater than about 96% toabout 99.5%, greater than about 97% to about 99.5%, greater than about98% to greater than about 99.5%, greater than about 99% to about 99.5%or more.

Individual stereoisomers of compounds of the present disclosure can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby: (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary; (2) salt formation employing an opticallyactive resolving agent; or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Stereoisomers can also be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentdisclosure. The present disclosure encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards. Unless otherwise specified, structures depicting doublebonds encompass both the E and Z isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangements of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The compounds disclosed herein may exist as tautomers and bothtautomeric forms are intended to be encompassed by the scope of thepresent disclosure, even if only one tautomeric structure is depicted.

Additionally, unless otherwise stated, structures described herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuterium(²H) or tritium (³H), or the replacement of a carbon by a ¹³C- or¹⁴C-carbon atom are within the scope of this disclosure. Such compoundsmay be useful as, for example, analytical tools, probes in biologicalassays, or therapeutic agents.

Compounds

In some embodiments, provided herein are compounds of Formula (1), or atautomer, stereoisomer, or pharmaceutically acceptable salt thereof, anddeuterated derivatives of any of the foregoing:

wherein:

X₁ is CR₁ or N;

X₂ is CR₂ or N;

X₃ is CR₃ or N;

X₄ is CR₄ or N;

each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkyl, each of which is substitutedwith 0, 1, 2, or 3 R_(S);

each R₅ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₆ is independently selected from hydrogen, C₁-C₃alkyl, andC₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3 R_(S);

each R₇ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₈ is independently selected from hydrogen, hydroxyl, C₁-C₃alkyl,and C₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3R_(S), or two R₈ groups are taken together to form an oxo;

each R₉ is independently selected from hydrogen, C₁-C₃alkyl,—C(═O)—(C₁-C₃alkyl), —C(═O)—O—(C₁-C₃alkyl), and —C(═O)—NH—(C₁-C₃alkyl),each of which is substituted with 0, 1, 2, or 3 R_(S), or two R₉ groupsare taken together to form a 3- to 6-membered heterocycle or heteroaryl;

each R_(S) is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN;

L is a linker of 1 to 16 carbon atoms in length, wherein one or morecarbon atoms are optionally replaced by C(═O), O, N(R₉), S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein theR₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are eachindependently substituted with 0, 1, 2, or 3 R_(S);

m is 0, 1, 2, or 3; and

n is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (1) may be a compound ofFormula (1A)

In some embodiments, provided herein are compounds of Formula (2), or atautomer, stereoisomer, or pharmaceutically acceptable salt thereof, anddeuterated derivatives of any of the foregoing:

wherein:

X₁ is CR₁ or N;

X₂ is CR₂ or N;

X₃ is CR₃ or N;

X₄ is CR₄ or N;

each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkyl, each of which is substitutedwith 0, 1, 2, or 3 R_(S);

each R₅ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₆ is independently selected from hydrogen, C₁-C₃alkyl, andC₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3 R_(S);

each R₇ is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which issubstituted with 0, 1, 2, or 3 R_(S);

each R₈ is independently selected from hydrogen, hydroxyl, C₁-C₃alkyl,and C₁-C₃haloalkyl, each of which is substituted with 0, 1, 2, or 3R_(S), or two R₈ groups are taken together to form an oxo;

each R₉ is independently selected from hydrogen, C₁-C₃alkyl,—C(═O)—(C₁-C₃alkyl), —C(═O)—O—(C₁-C₃alkyl), and —C(═O)—NH—(C₁-C₃alkyl),each of which is substituted with 0, 1, 2, or 3 R_(S), or two R₉ groupsare taken together to form a 3- to 6-membered heterocycle or heteroaryl;

each R_(S) is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN;

L is a linker of 1 to 16 carbon atoms in length, wherein one or morecarbon atoms are optionally replaced by C(O), O, N(R₉), S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein theR₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are eachindependently substituted with 0, 1, 2, or 3 R_(S);

m is 0, 1, or 2;

n is 0, 1, 2, or 3; and

o is 0, 1, 2, or 3.

In some embodiments, the compound of Formula (2) may be a compound ofFormula (2A)

In some embodiments, X₁ is N. In some embodiments, X₂ is N. In someembodiments, X₁ and X₂ are each N. In some embodiments, X₂ is CR₂, X₃ isCR₃, and X₄ is CR₄. In some embodiments, R₂, R₃, and R₄ are eachindependently selected from H and F. In some embodiments, X₂ is CR₂, X₃is CR₃, X₄ is CR₄, and R₂, R₃, and R₄ are each independently selectedfrom H and F. In some embodiments, X₁ is CR₁, X₂ is CR₂, X₃ is CR₃, andX₄ is CR₄. In some embodiments, R₁, R₂, R₃, and R₄ are eachindependently selected from H and F. In some embodiments, X₁ is CR₁, X₂is CR₂, X₃ is CR₃, and X₄ is CR₄, and R₁, R₂, R₃, and R₄ are eachindependently selected from H and F.

In some embodiments, R₁ is F. In some embodiments, R₂ is F. In someembodiments, R₃ is F. In some embodiments, R₁ and R₃ are each F. In someembodiments, R₃ and R₄ are each F. In some embodiments, R₂, R₃, and R₄are each H. In some embodiments, R₁, R₃, and R₄ are each H. In someembodiments, R₁, R₂, and R₄ are each H. In some embodiments, R₁, R₂, andR₃ are each H. In some embodiments, R₂ and R₄ are each H. In someembodiments, R₁ and R₂ are each H.

In some embodiments, the

group is selected from

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, each R₅ is independently selected from halogen,C₁-C₃alkoxy, and C₁-C₃haloalkyl. In some embodiments, each R₅ isindependently selected from —Cl, —OCH₃, and —CF₃.

In some embodiments, m is 1 or 2. In some embodiments, m is O. In someembodiments, m is 1. In some embodiments, m is 2.

In some embodiments, o is 0. In some embodiments, o is 1.

In some embodiments, m and o are each 0.

In some embodiments, each R₆ is independently selected from H andC₁-C₃alkyl. In some embodiments, each R₆ is independently selected fromH and —CH₃. In some embodiments, one R₆ is H and the other R₆ is —CH₃.In some embodiments, each R₆ is identical. In some embodiments, each R₆is different.

In some embodiments, the group

is selected from

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

is selected from

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, the group

In some embodiments, each R₇ is independently selected from halogen,hydroxyl, C₁-C₃alkyl, and C₁-C₃haloalkyl. In some embodiments, each R₇is independently selected from halogen, hydroxyl, —CH₃, and —CF₃. Insome embodiments, each R₇ is independently selected from F, hydroxyl,—CH₃, and —CF₃. In some embodiments, each R₇ is independently F.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, each R₈ is hydrogen or two R₈ groups are takentogether to form an oxo. In some embodiments, each R₈ is hydrogen. Insome embodiments, two R₈ groups are taken together to form an oxo.

In some embodiments, the

group is

In some embodiments, the

group is selected from

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, the

group is

In some embodiments, each R₉ is independently selected from hydrogen,C₁-C₃alkyl, and —C(═O)—C₁-C₃alkyl. In some embodiments, each R₉ isindependently selected from hydrogen and C₁-C₃alkyl. In someembodiments, each R₉ is independently selected from hydrogen, —CH₃,—CH₂CH₃, and —CH(CH₃)₂.

In some embodiments, L is a linker of 1 to 12 carbon atoms in length,wherein one or more carbon atoms are optionally replaced by C(═O), O,N(R₉), S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl, heterocycle, orheteroaryl, wherein the R₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle,and heteroaryl are each independently substituted with 0, 1, 2, or 3R_(S). In some embodiments, L is a linker of 1 to 10 carbon atoms inlength, wherein one or more carbon atoms are optionally replaced byC(═O), O, N(R₉), S, C₂-alkenyl, C₂-alkynyl, cycloalkyl, aryl,heterocycle, or heteroaryl, wherein the R₉, C₂-alkenyl, cycloalkyl,aryl, heterocycle, and heteroaryl are each independently substitutedwith 0, 1, 2, or 3 R_(S). In some embodiments, L is a linker of 1 to 8carbon atoms in length, carbon atoms in length, wherein one or morecarbon atoms are optionally replaced by C(═O), O, N(R₉), S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein theR₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are eachindependently substituted with 0, 1, 2, or 3 R_(S). In some embodiments,L is a linker of 1 to 6 carbon atoms in length, wherein one or morecarbon atoms are optionally replaced by C(═O), O, N(R₉), S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein theR₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are eachindependently substituted with 0, 1, 2, or 3 R_(S).

In some embodiments, one or more carbon atoms of linker L are optionallyreplaced by C(═O), O, N(R₉), S, cycloalkyl, aryl, heterocycle, orheteroaryl. In some embodiments, one or more carbon atoms of linker Lare optionally replaced by O, N(R₉), cycloalkyl, or heterocycle, whereinthe R₉, cycloalkyl, and heterocycle are each independently substitutedwith 0, 1, 2, or 3 R_(S).

In some embodiments, the heterocycle in L is selected from piperidineand piperazine, each of which is substituted with 0, 1, 2, or 3 R_(S).In some embodiments, the heterocycle in L is selected from

In some embodiments, L is selected from:

In some embodiments, provided herein is a pharmaceutically acceptablesalt of a compound of Formula (1) (e.g. Formula (1A)) or (2) (e.g.Formula (2A)). In some embodiments, provided herein is a deuteratedderivative of a pharmaceutically acceptable salt of a compound ofFormula (1) or (2). In some embodiments, provided herein is a compoundof Formula (1) or (2).

In some embodiments, provided herein is a compound chosen from thecompounds listed in Table 2 or a tautomer, stereoisomer, orpharmaceutically acceptable salt thereof, or a deuterated derivative ofany of the foregoing.

TABLE 2 Exemplary Compounds of the Present Disclosure Reference #Structure & Name Number  1

1-1   2

1-2   3

1-3   4

1-4   5

1-5   6

1-6   7

1-7   8

1-8   9

1-9  10

1-10 11

1-11 12

1-12 13

1-13 14

1-14 15

1-15 16

1-16 17

1-17 18

1-18 19

1-19 20

1-20 21

1-21 22

1-22 23

1-23 24

1-24 25

1-25 26

1-26 27

1-27 28

1-28 29

1-29 30

1-30 31

1-31 32

1-32 33

1-33 34

1-34 35

1-35 36

1-36 37

1-37 38

1-38 39

1-39 40

1-40 41

1-41 42

1-42 43

1-43 44

1-44 45

1-45 46

1-46 47

1-47 48

1-48 49

1-49 50

1-50 51

1-51 52

1-52 53

1-53 54

1-54 55

1-55 56

1-56

In some embodiments, provided herein is a compound chosen from thecompounds listed in Table 3 or a tautomer, stereoisomer, orpharmaceutically acceptable salt thereof, or a deuterated derivative ofany of the foregoing.

TABLE 3 Exemplary Compounds of the Present Disclosure Reference #Structure & Name Number 57

2-1  58

2-2  59

2-3  60

2-4  61

2-5  62

2-6  63

2-7  64

2-8  65

2-9  66

2-10 67

2-11 68

2-12 69

2-13 70

2-14 71

2-15 72

2-16 73

2-17 74

2-18 75

2-19 76

2-20 77

2-21 78

2-22 79

2-23 80

2-24 81

2-25 82

2-26 83

2-27 84

2-28 85

2-29 86

2-30Pharmaceutical Compositions

Pharmaceutical compositions of the present disclosure comprise at leastone compound of Formulae (1) (e.g. Formula (1A)) or (2) (e.g. Formula(2A)), or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, or a deuterated derivative of any of the foregoing formulatedtogether with a pharmaceutically acceptable carrier. These formulationsinclude those suitable for oral, rectal, topical, buccal and parenteral(e.g., subcutaneous, intramuscular, intradermal, or intravenous)administration. The most suitable form of administration in any givencase will depend on the degree and severity of the condition beingtreated and on the nature of the particular compound being used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of a compound of the presentdisclosure as powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. As indicated, such formulations may be prepared by anysuitable method of pharmacy which includes the step of bringing intoassociation at least one compound of the present disclosure as theactive compound and a carrier or excipient (which may constitute one ormore accessory ingredients). The carrier must be acceptable in the senseof being compatible with the other ingredients of the formulation andmust not be deleterious to the recipient. The carrier may be a solid ora liquid, or both, and may be formulated with at least one compounddescribed herein as the active compound in a unit-dose formulation, forexample, a tablet, which may contain from about 0.05% to about 95% byweight of the at least one active compound. Other pharmacologicallyactive substances may also be present including other compounds. Theformulations of the present disclosure may be prepared by any of thewell-known techniques of pharmacy consisting essentially of admixing thecomponents.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmacologicallyadministrable compositions can, for example, be prepared by, forexample, dissolving or dispersing, at least one active compound of thepresent disclosure as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. In general, suitable formulations may be prepared byuniformly and intimately admixing the at least one active compound ofthe present disclosure with a liquid or finely divided solid carrier, orboth, and then, if necessary, shaping the product. For example, a tabletmay be prepared by compressing or molding a powder or granules of atleast one compound of the present disclosure, which may be optionallycombined with one or more accessory ingredients. Compressed tablets maybe prepared by compressing, in a suitable machine, at least one compoundof the present disclosure in a free-flowing form, such as a powder orgranules, which may be optionally mixed with a binder, lubricant, inertdiluent and/or surface active/dispersing agent(s). Molded tablets may bemade by molding, in a suitable machine, where the powdered form of atleast one compound of the present disclosure is moistened with an inertliquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising at least one compound of the present disclosure in aflavored base, usually sucrose and acacia or tragacanth, and pastillescomprising the at least one compound in an inert base such as gelatinand glycerin or sucrose and acacia.

Formulations of the present disclosure suitable for parenteraladministration comprise sterile aqueous preparations of at least onecompound of Formula (1) (e.g. Formula (1A)) or (2) (e.g. Formula (2A)),or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, or a deuterated derivative of any of the foregoing, which areapproximately isotonic with the blood of the intended recipient. Thesepreparations are administered intravenously, although administration mayalso be affected by means of subcutaneous, intramuscular, or intradermalinjection. Such preparations may conveniently be prepared by admixing atleast one compound described herein with water and rendering theresulting solution sterile and isotonic with the blood. Injectablecompositions according to the present disclosure may contain from about0.1 to about 5% w/w of the active compound.

Formulations suitable for rectal administration are presented asunit-dose suppositories. These may be prepared by admixing at least onecompound as described herein with one or more conventional solidcarriers, for example, cocoa butter, and then shaping the resultingmixture.

Formulations suitable for topical application to the skin may take theform of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.Carriers and excipients which may be used include Vaseline, lanoline,polyethylene glycols, alcohols, and combinations of two or more thereof.The active compound (i.e., at least one compound of Formula (1) (e.g.Formula (1A)) or (2) (e.g. Formula (2A)), or a tautomer, stereoisomer,or pharmaceutically acceptable salt thereof, or a deuterated derivativeof any of the foregoing) is generally present at a concentration of fromabout 0.1% to about 15% w/w of the composition, for example, from about0.5 to about 2%.

The amount of active compound administered may be dependent on thesubject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician. Forexample, a dosing schedule may involve the daily or semi-dailyadministration of the encapsulated compound at a perceived dosage ofabout 1 μg to about 1000 mg. In another embodiment, intermittentadministration, such as on a monthly or yearly basis, of a dose of theencapsulated compound may be employed. Encapsulation facilitates accessto the site of action and allows the administration of the activeingredients simultaneously, in theory producing a synergistic effect. Inaccordance with standard dosing regimens, physicians will readilydetermine optimum dosages and will be able to readily modifyadministration to achieve such dosages.

A therapeutically effective amount of a compound or compositiondisclosed herein can be measured by the therapeutic effectiveness of thecompound. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being used. In one embodiment, thetherapeutically effective amount of a disclosed compound is sufficientto establish a maximal plasma concentration. Preliminary doses as, forexample, determined according to animal tests, and the scaling ofdosages for human administration is performed according to art-acceptedpractices.

Toxicity and therapeutic efficacy can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferable.

Data obtained from the cell culture assays or animal studies can be usedin formulating a range of dosage for use in humans. Therapeuticallyeffective dosages achieved in one animal model may be converted for usein another animal, including humans, using conversion factors known inthe art (see, e.g., Freireich et al., Cancer Chemother. Reports50(4):219-244 (1966) and the following table (Table 4) for EquivalentSurface Area Dosage Factors).

TABLE 4 To: Mouse Rat Monkey Dog Human From: (20 g) (150 g) (3.5 kg) (8kg) (60 kg) Mouse 1 ½ ¼ ⅙   1/12 Rat 2 1 ½ ¼ 1/7 Monkey 4 2 1 ⅗ ⅓ Dog 64 ⅗ 1 ½ Human 12 7 3 2 1

The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized.Generally, a therapeutically effective amount may vary with thesubject's age, condition, and gender, as well as the severity of themedical condition in the subject. The dosage may be determined by aphysician and adjusted, as necessary, to suit observed effects of thetreatment.

Methods of Treatment

In some embodiments, a compound of Formula (1) (e.g. Formula (1A)) or(2) (e.g. Formula (2A)), or a tautomer, stereoisomer, orpharmaceutically acceptable salt thereof, or a deuterated derivative ofany of the foregoing, is administered to treat cancer in a subject inneed thereof. In some embodiments, the cancer is chosen from prostatecancer, head and neck cancer, skin cancer, sarcoma, renal cellcarcinoma, adrenocortical carcinoma, bladder cancer, lung cancer,gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma,colorectal cancer, connective tissue cancer, glioblastoma multiforme,cervical cancer, uterine cancer, ovarian cancer, and breast cancer. Insome embodiments, the cancer is prostate cancer. In some embodiments,the cancer is head and neck cancer. In some embodiments, the cancer isskin cancer. In some embodiments, the cancer is sarcoma. In someembodiments, the cancer is renal cell carcinoma. In some embodiments,the cancer is adrenocortical carcinoma. In some embodiments, the canceris bladder cancer. In some embodiments, the cancer is lung cancer. Insome embodiments, the cancer is gastric carcinoma. In some embodiments,the cancer is esophageal carcinoma. In some embodiments, the cancer ispancreatic adenocarcinoma. In some embodiments, the cancer is colorectalcancer. In some embodiments, the cancer is connective tissue cancer. Insome embodiments, the cancer is glioblastoma multiforme. In someembodiments, the cancer is cervical cancer. In some embodiments, thecancer is uterine cancer. In some embodiments, the cancer is ovariancancer. In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is androgen receptor positive.

In some embodiments, a compound of Formulae (1) (e.g. Formula (1A)) or(2) (e.g. Formula (2A)), or a tautomer, stereoisomer, orpharmaceutically acceptable salt thereof, or a deuterated derivative ofany of the foregoing, is administered as a pharmaceutical composition.

In some embodiments, the subject has been previously treated with ananti-cancer agent. In some embodiments, the anti-cancer agent isenzalutamide, apalutamide, bicalutamide, darolutamide, flutamide,abiratarone, or a combination of any of the foregoing. In someembodiments, the anti-cancer agent is enzalutamide.

In some embodiments, provided herein is a use of a compound of Formula(1) (e.g. Formula (1A)) or (2) (e.g. Formula (2A)), or a tautomer,stereoisomer, or pharmaceutically acceptable salt thereof, or adeuterated derivative of any of the foregoing, for treating cancer. Insome embodiments, the cancer is selected from prostate cancer, head andneck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocorticalcarcinoma, bladder cancer, lung cancer, gastric carcinoma, esophagealcarcinoma, pancreatic adenocarcinoma, colorectal cancer, connectivetissue cancer, glioblastoma multiforme, cervical cancer, uterine cancer,ovarian cancer, and breast cancer. In some embodiments, the cancer isprostate cancer. In some embodiments, the cancer is head and neckcancer. In some embodiments, the cancer is skin cancer. In someembodiments, the cancer is sarcoma. In some embodiments, the cancer isrenal cell carcinoma. In some embodiments, the cancer is adrenocorticalcarcinoma. In some embodiments, the cancer is bladder cancer. In someembodiments, the cancer is lung cancer. In some embodiments, the canceris gastric carcinoma. In some embodiments, the cancer is esophagealcarcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma.In some embodiments, the cancer is colorectal cancer. In someembodiments, the cancer is connective tissue cancer. In someembodiments, the cancer is glioblastoma multiforme. In some embodiments,the cancer is cervical cancer. In some embodiments, the cancer isuterine cancer. In some embodiments, the cancer is ovarian cancer. Insome embodiments, the cancer is breast cancer. In some embodiments, thecancer is androgen receptor positive.

In some embodiments, provided herein is a use of a compound of Formula(1) or (2), or a tautomer, stereoisomer, or pharmaceutically acceptablesalt thereof, or a deuterated derivative of any of the foregoing, in thepreparation of a medicament. In some embodiments, the medicament is forthe treatment of cancer. In some embodiments, the cancer is selectedfrom prostate cancer, head and neck cancer, skin cancer, sarcoma, renalcell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer,gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma,colorectal cancer, connective tissue cancer, glioblastoma multiforme,cervical cancer, uterine cancer, ovarian cancer, and breast cancer. Insome embodiments, the cancer is prostate cancer. In some embodiments,the cancer is head and neck cancer. In some embodiments, the cancer isskin cancer. In some embodiments, the cancer is sarcoma. In someembodiments, the cancer is renal cell carcinoma. In some embodiments,the cancer is adrenocortical carcinoma. In some embodiments, the canceris bladder cancer. In some embodiments, the cancer is lung cancer. Insome embodiments, the cancer is gastric carcinoma. In some embodiments,the cancer is esophageal carcinoma. In some embodiments, the cancer ispancreatic adenocarcinoma. In some embodiments, the cancer is colorectalcancer. In some embodiments, the cancer is connective tissue cancer. Insome embodiments, the cancer is glioblastoma multiforme. In someembodiments, the cancer is cervical cancer. In some embodiments, thecancer is uterine cancer. In some embodiments, the cancer is ovariancancer. In some embodiments, the cancer is breast cancer. In someembodiments, the cancer is androgen receptor positive.

In some embodiments, provided herein is a method of inhibiting cellgrowth comprising contacting a cell with a compound of Formula (1) (e.g.Formula (1A)) or (2) (e.g. Formula (2A)), or a tautomer, stereoisomer,or pharmaceutically acceptable salt thereof, or a deuterated derivativeof any of the foregoing. In some embodiments, the cell is a cancer cell.In some embodiments, the cancer cell is a prostate cancer cell. In someembodiments, the cell is androgen receptor positive.

In one embodiment, a compound of Formula (1) (e.g. Formula (1A)) or (2)(e.g. Formula (2A)), or a tautomer, stereoisomer, pharmaceuticallyacceptable salt or hydrate thereof, may be administered in combinationwith another therapeutic agent. The other therapeutic agent can provideadditive or synergistic value relative to the administration of acompound of the present disclosure alone. The therapeutic agent can beselected from, for example, hormones and hormonal analogues; signaltransduction pathway inhibitors; topoisomerase I inhibitors;topoisomerase II inhibitors; antimetabolite neoplastic agents;antibiotic neoplastic agents; alkylating agents; anti-microtubuleagents; platinum coordination complexes; aromatase inhibitors; andanti-mitotic agents.

In some embodiments, the therapeutic agent may be a hormone or hormonalanalogue. In some embodiments, the therapeutic agent may be a signaltransduction pathway inhibitor. In some embodiments, the therapeuticagent may be a topoisomerase I inhibitor. In some embodiments, thetherapeutic agent may be a topoisomerase II inhibitor. In someembodiments, the therapeutic agent may be an antimetabolite neoplasticagent. In some embodiments, the therapeutic agent may be an antibioticneoplastic agent. In some embodiments, the therapeutic agent may be analkylating agent. In some embodiments, the therapeutic agent may be ananti-microtubule agent. In some embodiments, the therapeutic agent maybe a platinum coordination complex. In some embodiments, the therapeuticagent may be an aromatase inhibitor. In some embodiments, thetherapeutic agent may be an anti-mitotic agent.

In some embodiments, the aromatase inhibitor may be selected fromanastrazole, letrozole, vorozole, fadrozole, exemestane, and formestane.In some embodiments, the aromatase inhibitor is anastrazole. In someembodiments, the aromatase inhibitor may be letrozole. In someembodiments, the aromatase inhibitor may be vorozole. In someembodiments, the aromatase inhibitor may be fadrozole. In someembodiments, the aromatase inhibitor may be exemestane. In someembodiments, the aromatase inhibitor may be formestane.

In some embodiments, the anti-mitotic agent may be selected frompaclitaxel, docetaxel, and Abraxane. In some embodiments, theanti-mitotic agent may be paclitaxel. In some embodiments, theanti-mitotic agent may be docetaxel. In some embodiments, theanti-mitotic agent may be Abraxane.

In some embodiments, a compound of Formula (1) (e.g. Formula (1A)) or(2) (e.g. Formula (2A)), or a tautomer, stereoisomer, orpharmaceutically acceptable salt thereof, or a deuterated derivative ofany of the foregoing, may be administered in combination with a hormoneor hormonal analog. In some embodiments, a compound of Formula (1) or(2), or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, or a deuterated derivative of any of the foregoing, may beadministered in combination with a signal transduction pathwayinhibitor. In some embodiments, a compound of Formula (1) or (2), or atautomer, stereoisomer, or pharmaceutically acceptable salt thereof, ora deuterated derivative of any of the foregoing, may be administered incombination with an antimetabolite neoplastic agent. In someembodiments, a compound of Formulae (1) or (2), or a tautomer,stereoisomer, or pharmaceutically acceptable salt thereof, or adeuterated derivative of any of the foregoing, may be administered incombination with a topoisomerase I inhibitor. In some embodiments, acompound of Formula (1) or (2), or a tautomer, stereoisomer, orpharmaceutically acceptable salt thereof, or a deuterated derivative ofany of the foregoing, may be administered in combination with atopoisomerase II inhibitor. In some embodiments, a compound of Formula(1) or (2), or a tautomer, stereoisomer, or pharmaceutically acceptablesalt thereof, or a deuterated derivative of any of the foregoing, may beadministered in combination with an aromatase inhibitor.

Examples

The examples and preparations provided below further illustrate andexemplify the compounds as disclosed herein and methods of preparingsuch compounds. It is to be understood that the scope of the presentdisclosure is not limited in any way by the scope of the followingexamples and preparations.

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques well known inthe art. Unless specified to the contrary, the reactions describedherein take place at atmospheric pressure, generally within atemperature range from about −10° C. to about 200° C. Further, except asotherwise specified, reaction times and conditions are intended to beapproximate, e.g., taking place at about atmospheric pressure within atemperature range of about −10° C. to about 200° C. over a period thatcan be, for example, about 1 to about 24 hours; reactions left to runovernight in some embodiments can average a period of about 16 hours.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be affected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures. See,e.g., Carey et al. Advanced Organic Chemistry, 3^(rd) Ed., 1990 NewYork: Plenum Press; Mundy et al., Name Reaction and Reagents in OrganicSynthesis, 2^(nd) Ed., 2005 Hoboken, N.J.: J. Wiley & Sons. Specificillustrations of suitable separation and isolation procedures are givenby reference to the examples hereinbelow. However, other equivalentseparation or isolation procedures can also be used.

In all of the methods, it is well understood that protecting groups forsensitive or reactive groups may be employed where necessary, inaccordance with general principles of chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Greene and P. G. M. Wuts (1999) Protective Groups in Organic Synthesis,3^(rd) Ed., John Wiley & Sons). These groups may be removed at aconvenient stage of the compound synthesis using methods that arereadily apparent to those skilled in the art.

When desired, the (R)- and (S)-isomers of the nonlimiting exemplarycompounds, if present, can be resolved by methods known to those skilledin the art, for example, by formation of diastereoisomeric salts orcomplexes which can be separated, e.g., by crystallization; viaformation of diastereoisomeric derivatives which can be separated, e.g.,by crystallization, gas-liquid or liquid chromatography; selectivereaction of one enantiomer with an enantiomer-specific reagent, e.g.,enzymatic oxidation or reduction, followed by separation of the modifiedand unmodified enantiomers; or gas-liquid or liquid chromatography in achiral environment, e.g., on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent.Alternatively, a specific enantiomer can be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer to the other by asymmetrictransformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Also, the compounds described herein can be optionally contactedwith a pharmaceutically acceptable base to form the corresponding basicaddition salts.

In some embodiments, disclosed compounds can generally be synthesized byan appropriate combination of generally well-known synthetic methods.Techniques useful in synthesizing these chemical entities are bothreadily apparent and accessible to those of skill in the relevant art,based on the instant disclosure. Many of the optionally substitutedstarting compounds and other reactants are commercially available, e.g.,from Millipore Sigma or can be readily prepared by those skilled in theart using commonly employed synthetic methodology.

The discussion below is offered to illustrate certain of the diversemethods available for use in making the disclosed compounds and is notintended to limit the scope of reactions or reaction sequences that canbe used in preparing the compounds provided herein. The skilled artisanwill understand that standard atom valencies apply to all compoundsdisclosed herein in genus or named compound for unless otherwisespecified.

All final compounds of the examples described herein were checked forpurity by HPLC on a Shimadzu LC-2010A and compounds were detected at thewavelength of 214 nM and 254 nM. Purities for all final compounds wereover 95% based on HPLC peaks (214 nM and 254 nM wavelength). Liquidchromatography condition: Column, XBRIDGE C18, 3.6 micron, 2.1×50 mm:Mobile phase, water (0.05% TFA) and acetonitrile (0.05% TFA), lineargradient from 10% acetonitrile to 100% acetonitrile over 7 min; Oventemperature 45° C.; Flow rate, 0.8 mL/mL. H-NMR was obtained on Bruker400 MHz NMR spectrometer.

General Synthetic Schemes

Compounds of Formula (1) ((e.g. Formula (1A)), see compounds in Table 2)can be prepared according to the following schemes. The followingschemes represent the general methods used in preparing these compounds.However, the synthesis of these compounds is not limited to theserepresentative methods, as they can also be prepared by various othermethods those skilled in the art of synthetic chemistry, for example, ina stepwise or modular fashion.

Compound 1-2 can be synthesized according to the method described inScheme 1.

Compounds 1-3, 1-4, 1-5 can be prepared by a method similar to the onedescribed in Scheme 2.

Compounds 1-8, 1-9, 1-11 and 1-12 can be prepared by a method similar tothe one described in Scheme 4.

The following compounds can be prepared by a method similar to the onedescribed in Scheme 5: 1-13, 1-15, 1-16, 1-17, 1-18, 1-20, 1-21, 1-22,1-23, 1-24, 1-25, 1-26, 1-27, 1-30, 1-31, 1-36, 1-37, 1-45, 1-47, and1-48.

1-19 can be prepared by a method similar to the one described in Scheme6.

1-38 can be prepared by a method similar to the one described in Scheme7.

Compounds 1-39 and 1-41 can be prepared by a method similar to the onedescribed in Scheme 8.

The following compounds can be synthesized according to the syntheticmethod described in Scheme 9: 1-32, 1-33, 1-34, 1-35, 1-40, 1-42, 1-43,1-44, 1-49, 1-50, 1-51, 1-52, 1-53.

Compounds of Formula (2) ((e.g. Formula (2A)); see compounds describedin Table 3) can be prepared according to the following schemes. Thefollowing schemes represent the general methods used in preparing thesecompounds. However, the synthesis of these compounds is not limited tothese representative methods, as they can also be prepared by variousother methods those skilled in the art of synthetic chemistry, forexample, in a stepwise or modular fashion.

Compound 2-2 can be synthesized according to the synthetic methoddescribed in Scheme 10.

Compounds 2-3, 2-4, 2-5 were synthesized according to the syntheticmethod described in Scheme 11.

Compounds 2-8, 2-12, 2-15, and 2-16 can be synthesized according to thesynthetic method described in Scheme 13.

The following compounds can be synthesized according to the syntheticmethod described in Scheme 15: 2-10, 2-11, 2-18, 2-28, 2-29, and 2-30.

The following compounds can be synthesized according to the syntheticmethod described in Scheme 16: 2-14, 2-25, 2-26, and 2-27.

Compound 2-19 was synthesized using the same method as described inScheme 17.

Compounds 2-23 and 2-24 were synthesized using the same method asdescribed in Scheme 18.

Abbreviations

The following abbreviations have the meanings set forth below:

ACN: acetonitrile

EtOAc: ethyl acetate

PE: petroleum ether

TFA: trifluoroacetic acid

AcOH: acetic acid

NaCNBH3: sodium cyanoborohydride

DMAP: 4-dimethylaminopyridine

DMSO: dimethyl sulfoxide

DCM: dichloromethane

TEA: triethylamine

AcOH: acetic acid

AcONa: Sodium acetate

EtOH: ethanol Pd₂(dba)₃: tri(dibenzylideneacetone)dipalladium

EA: ethyl acetate

S-Phos: 2-dicyclohexylphosphino-2′, 6′-dimethoxybiphenyl

Pd/C: palladium on activated carbon TLC: thin layer chromatography

Compounds described herein were prepared from commercially availablematerial. Purity of all final compounds were analyzed by HPLC withdetection at 214 nM and 254 nM wavelength. All final compounds showedpurity greater than 95%. All final compounds were characterized by LC/MSand H-NMR. The following are representative examples demonstrating howthe claimed molecules can be made, however, a person of skill in the artwould understand that the compounds could be prepared by other syntheticmethods.

Preparation of Intermediates Synthesis of2-chloro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)benzonitrile(Intermediate 1-1)

Step 1: Preparation of tert-butyl(2R,5S)-4-(3-chloro-4-cyanophenyl)-2,5-dimethylpiperazine-1-carboxylate

To a solution of 2-chloro-4-fluorobenzonitrile (5 g, 32.14 mmol) inDMSO/Water (10:1, 55 mL) was added K₂CO₃ (8.9 g, 64.28 mmol) andtert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (6.9 g, 32.14mmol). The reaction mixture was stirred at 80° C. for 12 hours. Themixture was cooled to room temperature, quenched by adding H₂O (50 mL),then extracted by EtOAc (100 mL×2). The combined organic layer waswashed by brine, dried and concentrated under vacuum to get the crudeproduct, which was purified by flash column chromatography (10% MeOH inDCM) to give the desired product (6.2 g, 55.1%) as a yellow oil. LC/MS:349.9 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J=1.2 Hz, 1H), 6.83 (d,J=2.4 Hz, 1H), 6.71 (dd, J=8.8, 2.4 Hz, 1H), 4.55-4.25 (m, 1H),4.06-3.96 (m, 1H), 3.92-3.77 (m, 1H), 3.44-3.38 (m, 1H), 3.37-3.27 (m,2H), 1.51 (s, 9H), 1.25 (d, J=6.4 Hz, 3H), 1.17 (d, J=6.4 Hz, 3H).

Step 2: Preparation of2-chloro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)benzonitrile

Tert-butyl(2R,5S)-4-(3-chloro-4-cyanophenyl)-2,5-dimethylpiperazine-1-carboxylate(6.2 g, 17.72 mmol) was stirred in HCl/EtOH (2 M, 50 mL) at roomtemperature for 2 hours. After the removal of EtOH, 100 mL of water wasadded, and the solution was adjusted to pH about 8 with aqueous Na₂CO₃.The mixture was extracted with EtOAc (100 mL×2). The combined organiclayer was washed with brine, dried and concentrated under vacuum to getthe crude product, which was purified by flash chromatography (10% MeOHin DCM) to give the desired product (3.8 g, 85.9%) as a yellow oil.LC/MS: 249.9 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=4.8 Hz, 1H),6.87 (d, J=2.4 Hz, 1H), 6.75 (dd, J=8.8, 2.4 Hz, 1H), 3.73-3.67 (m, 1H),3.35-3.27 (m, 3H), 3.09-3.04 (m, 1H), 2.71 (dd, J=12.8 4.4 Hz, 1H), 1.61(s, 1H), 1.21 (d, J=4.8 Hz, 3H), 1.19 (d, J=4.8 Hz, 3H).

Synthesis of 2-chloro-4-(trans-2,5-dimethylpiperazin-1-yl)benzonitrile(intermediate 1-2)

To a solution of 2-chloro-4-fluorobenzonitrile (1 g, 6.43 mmol) inDMSO/Water (10:1, 11 mL) was added K₂CO₃ (1.78 g, 12.86 mmol) andtrans-2,5-dimethylpiperazine (771 mg, 6.75 mmol). The reaction mixturewas stirred at 80° C. for 12 hours. The mixture was cooled to roomtemperature, quenched with H₂O (50 mL), then extracted by EtOAc (100mL×2). The combined organic layer was washed with brine, dried andconcentrated under vacuum to give a crude product, which was purified bysilica gel flash column chromatography (10% MeOH in DCM) to give thedesired product (540 mg, 31.88%) as a yellow oil. LC/MS: 250.2 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J=8.8 Hz, 1H), 6.88 (d, J=2.4 Hz,1H), 6.76 (dd, J=8.8, 2.4 Hz, 1H), 3.75-3.68 (m, 1H), 3.35-3.29 (m, 3H),3.10-3.05 (m, 1H), 2.72 (dd, J=12.6, 4.4 Hz, 1H), 2.10 (s, 1H), 1.22 (d,J=6.8 Hz, 3H), 1.20 (d, J=6.8 Hz, 3H).

Synthesis of 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-2-methoxybenzonitrile (Intermediate 1-3)

Step 1: Preparation of 4-bromo-2-methoxybenzonitrile

A mixture of 4-bromo-2-fluorobenzonitrile (5 g, 0.025 mol), CH₃ONa (2.7g, 0.05 mol) and MeOH (100 mL) was stirred at room temperatureovernight. The crude product was concentrated and purified via silicagel column chromatography (DCM/MeOH=20:1) to give the title compound(2.4 g, 90% purity, 40%). LC/MS: 211.9 [M+H]⁺.

Step 2: Preparation of tert-butyl(2R,5S)-4-(4-cyano-3-methoxyphenyl)-2,5-dimethylpiperazine-1-carboxylate

To a solution 4-bromo-2-methoxybenzonitrile (1400 mg, 6.6 mmol) indioxane (50 mL) stirred under argon at room temperature was addedtert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (1415 mg, 6.6mmol), Pd₂(dba)₃ (181 mg, 0.20 mmol), potassium tert-butoxide (1481 mg,13.2 mmol) and S-Phos (89 mg, 0.06 mmol). The reaction mixture wasstirred at room temperature for 3 hours. The crude product was purifiedvia silica gel column chromatography (DCM/MeOH=20:1) to give the titlecompound (550 mg, 24%). LC/MS: 346.21[M+H]t Step 3: Preparation of4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-2-methoxy benzonitrile(Intermediate 1-3)

To a solution of tert-butyl(2R,5S)-4-(4-cyano-3-methoxyphenyl)-2,5-dimethylpiperazine-1-carboxylate(90 mg, 0.26 mmol) in DCM (20 mL) stirred under argon at roomtemperature was added TFA (90 mg, 0.78 mmol). The reaction mixture wasstirred at room temperature for 2 hours. The crude product wasconcentrated in vacuum to give the title compound as TFA salt (70 mg,88%). LC/MS: 246.15 [M+H]⁺.

Synthesis of4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-2-(trifluoromethyl)benzonitrilehydrochloride (Intermediate 1-4)

To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (441 mg, 2.33mmol), tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (500 mg,2.33 mmol)) in DMSO/H₂O (20 mL/10 mL) was added K₂CO₃ (644 mg, 4.66mmol). The reaction mixture was stirred at 80° C. for overnight. Thereaction mixture was cooled to room temperature and diluted with H₂O (20mL), then extracted with EA (20 mL×3), dried over Na₂SO₄ andconcentrated in vacuum to give a crude product. The crude product waspurified by silica gel chromatography (PE:EA=5:1) to give tert-butyl(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dimethylpiperazine-1-carboxylate(804 mg, 90%). LC/MS: 384.1 [M+H]⁺. This product (804 mg, 2.09 mmol) inEtOH (20 mL) was bubbled with HCl (g) for 10 minutes. The reactionmixture was stirred at room temperature for 2 hours. The solvent wasremoved in vacuum to give a crude product. The crude product was washedwith EA (5 mL×3) and dried in vacuum to give the title compound (287 mg,43%) as a hydrochloride salt. LC/MS: 283.9 [M+H]⁺; ¹H NMR (400 MHz,MeOD) δ 7.84 (d, J=8.7 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.34 (dd, J=8.7,2.5 Hz, 1H), 4.38-4.28 (m, 1H), 3.83-3.80 (m, 1H), 3.67-3.57 (m, 3H),3.23-3.19 (dd, J=13.3, 4.6 Hz, 1H), 1.45 (d, J=6.8 Hz, 3H), 1.31 (d,J=6.7 Hz, 3H).

Synthesis of5-((2S,5R)-2,5-dimethylpiperazin-1-yl)quinoline-8-carbonitrile(Intermediate 1-5)

To a solution of 5-bromoquinoline-8-carbonitrile (1.3 g, 5.6 mmol) andtert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (1 g, 4.67 mmol)in toluene (25 mL) stirred under nitrogen at room temperature was addedS-phos (192 mg, 0.467 mmol), Pd₂(dba)₃ (268 mg, 0.467 mmol) and t-BuONa(672 mg, 7 mmol). The reaction mixture was stirred at room temperaturefor 4 hours. The solvent was removed in vacuum to give a crude productwhich was purified by silica gel column chromatography (0-15% MeOH inDCM) to give tert-butyl(2R,5S)-4-(8-cyanoquinolin-5-yl)-2,5-dimethylpiperazine-1-carboxylate(1.2 g, 58%). LC/MS: 366.9 [M+H]⁺. This product (1.2 g, 3.27 mmol) inDCM (21 mL) was treated with trifluoroacetic acid (7 mL) and the mixturewas stirred at room temperature for 5 h. The solvent was removed invacuum to give the title compound (860 mg, 100%). LC/MS: 266.9 [M+H]⁺;¹H NMR (400 MHz, DMSO) δ 9.56 (d, J=9.1 Hz, 1H), 9.24 (d, J=10.0 Hz,1H), 9.10 (dd, J=4.2, 1.7 Hz, 1H), 8.85 (dd, J=8.6, 1.7 Hz, 1H), 8.38(dd, J=7.5, 4.3 Hz, 1H), 7.74 (dd, J=8.6, 4.2 Hz, 1H), 7.57 (d, J=8.0Hz, 1H), 3.76-3.58 (m, 2H), 3.53 (d, J=10.7 Hz, 1H), 3.28-3.18 (m, 1H),3.01 (q, J=10.6 Hz, 1H), 2.86-2.71 (m, 1H), 1.23 (d, J=6.5 Hz, 3H), 0.88(d, J=6.1 Hz, 3H).

Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione(Intermediate 2-1)

Intermediate 2-1 was prepared according to the above scheme as ahydrochloride salt using a similar method described in the literature.LC/MS 343.1 [M+H]⁺; ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.76 (d, J=8.36 Hz,1H), 7.47 (s, 1H), 7.35 (dd, J=8.36, 1.54 Hz, 1H), 5.09 (br dd, J=12.8,5.40 Hz, 1H), 3.67-3.74 (m, 4H), 3.37-3.42 (m, 4H), 2.63-2.94 (m, 3H),2.07-2.17 (m, 1H).

Synthesis of(S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione(Intermediate 2-2)

To a solution of (S)-tert-butyl4-(2-(1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate(5.8 g, 12 mol) in acetonitrile (90 mL) was added benzenesulfonic acid(3.64 g, 23 mol). The mixture was stirred at 85° C. for 12 h. LC/MSshowed the reaction was complete. The mixture was concentrated invacuum. The residue was triturated with ethyl acetate to afford(S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonate (5.2 g, 93%) as off-white solid. LC/MS 329.1 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d6) δ 1.95-1.99 (m, 1H), 2.36-2.41 (m, 1H), 2.58-2.62(d, 1H), 2.88-2.91 (m, 1H), 3.26 (s, 4H), 3.49-3.52 (m, 4H), 4.21-4.38(dd, 2H), 5.05-5.10 (dd, 1H), 7.12-7.16 (m, 2H), 7.30-7.358 (m, 3H),7.58-7.62 (m, 3H), 8.72 (s, 2H).

Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione(Intermediate 2-3)

Intermediate 2-3 was prepared using the similar method as Intermediate2-1 as a hydrochloride salt. LC/MS 361.1 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d6) δ 11.1 (s, 1H), 9.49 (br s, 2H), 7.79 (d, J=11.2 Hz, 1H), 7.57(br d, J=7.32 Hz, 1H), 5.12 (br dd, J=12.4, 5.32 Hz, 1H), 3.50 (br s,4H), 3.24 (br s, 4H), 2.80-2.95 (m, 1H), 2.52-2.69 (m, 2H), 1.97-2.10(m, 1H).

Synthesis of(S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione(Intermediate 2-4)

Step 1: Preparation of methyl 2-bromo-4,5-difluorobenzoate

Thionyl chloride (130 g, 1.09 mol) was added slowly to a mixture of2-bromo-4,5-difluorobenzoic acid (200 g, 0.84 mol) in MeOH (600 mL) at10° C., the mixture was stirred at 80° C. for 3 h. TLC showed thereaction was completed. The mixture was cooled to room temperature,concentrated, then partitioned between ethyl acetate and water. Theorganic layer was washed with saturated Na₂CO₃ and brine twice, driedover Na₂SO₄ and concentrated to afford a crude methyl2-bromo-4,5-difluorobenzoate (210 g, yield: 100%) which was used for thenext step without further purification.

Step 2: Preparation of tert-butyl4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl) piperazine-1-carboxylate

A mixture of methyl 2-bromo-4,5-difluorobenzoate (210 g, 0.84 mol),tert-butyl piperazine-1-carboxylate (234 g, 1.25 mol) and K₂CO₃ (173 g,1.25 mol) in N,N-dimethylacetamide (600 mL) was stirred at 80° C. for 16h. TLC showed the reaction was completed. The mixture was added to water(2 L) and stirred for 10 min followed by the addition of ethyl acetate.The mixture was partitioned between ethyl acetate and water. The organiclayer was washed with water, brine, dried over Na₂SO₄ and concentratedto afford tert-butyl4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(315.8 g, yield: 90%).

Step 3: Preparation of tert-butyl4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl) piperazine-1-carboxylate

A mixture of tert-butyl4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(306 g, 0.73 mol) and CuCN (98 g, 1.09 mol) in DMF (1.2 L) was stirredat 100° C. for 16 h. TLC showed the reaction was completed. The mixturewas cooled to room temperature. Ethyl acetate (2 L) and ammoniumhydroxide (2 L) were added and the mixture was stirred for 30 min. Themixture was filtered. The organic layer was washed with water, driedover Na₂SO₄ and concentrated to afford a crude product (254 g). Thiscrude product was taken into petroleum ether (1 L) at reflux. Themixture was filtered and dried in oven at 50° C. to afford tert-butyl4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(215 g, yield: 81%).

Step 4: Preparation of tert-butyl4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl) piperazine-1-carboxylate

To a solution of pyridine (391 g, 4.95 mol), water (200 mL), acetic acid(264 g, 4.4 mol) was added tert-butyl4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(200 g, 0.55 mol) and Raney-nickel (85% in water, 100 g) at roomtemperature. The resulting mixture was heated to 60° C. Sodiumhypophosphite (292 g in 500 mL water) was added dropwise into themixture. The mixture was stirred for 16 h at 60° C. TLC showed thereaction not completed. The mixture was further stirred for 10 h. Themixture was cooled to room temperature. Ethyl acetate and water wereadded. The mixture was filtered. The organic layer was washed withwater, 1N HCl and brine, dried over Na₂SO₄ and concentrated underreduced pressure to afford a crude product (208 g, crude) which wasfurther purified by silica-gel pad to provide4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(86.5 g, yield: 43%).

Step 5: Preparation of tert-butyl(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(2-fluoro-5-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate(81.5 g, 0.22 mol) in methanol (500 mL) was added tert-butyl(S)-4,5-diamino-5-oxopentanoate (54 g, 0.27 mol) at room temperature.Acetic acid (19.8 g, 0.33 mol) was added at 0° C. followed by theaddition of sodium cyanoborohydride (27.6 g, 0.44 mol) slowly. Themixture was stirred at room temperature for 16 hours. TLC showed thereaction was completed. The mixture was concentrated and partitionedbetween ethyl acetate and water. The organic layer was washed withsaturated citric acid, brine, dried over Na₂SO₄ and concentrated underreduced pressure to afford a crude product which was further purified bysilica-gel pad to give tert-butyl(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate(80 g, yield: 69%).

Step 6: Preparation of(S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonic acid (Intermediate 2-4)

To a solution of(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1-carboxylate(67 g, 0.13 mol) in acetonitrile (670 mL) was added benzenesulfonic acid(43 g, 0.26 mol). The mixture was stirred at 80° C. for 16 h. LCMSshowed the reaction was complete. The mixture was cooled to roomtemperature. The mixture was filtered and dried to afford(S)-3-(6-fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dionebenzenesulfonic acid (56 g, 86%) as off-white solid. ¹H NMR (400 MHz,DMSO-d6) δ 1.94-1.99 (m, 1H), 2.35-2.43 (m, 1H), 2.58-2.62 (m, 1H),2.88-2.91 (m, 1H), 3.30 (br s, 8H), 4.38 (d, J=17.2 Hz, 1H), 4.26 (d,J=17.2 Hz, 1H), 5.08 (dd, J=13.2, 5.2 Hz, 1H), 7.29-7.35 (m, 4H), 7.49(d, J=8.7 Hz, 1H), 7.60 (m, 2H), 8.72 (br s, 2H), 10.99 (s, 1H). LCMSm/z 347.3 [M+1]⁺.

Preparation of Example Compounds Synthesis of(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(((1r,3r)-3((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)butoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-8)

Step 1: Preparation of 2-(4,4-dimethoxybutoxy)-5-nitropyridine

The NaH (0.36 g, 15.19 mmol) was added in a mixture of THF (30 mL) and4,4-dimethoxybutan-1-ol (1.7 g, 12.7 mmol) at 0° C. After 30 minutes,2-chloro-5-nitropyridine (1 g, 6.33 mmol) was added. The reactionmixture was stirred at room temperature for 2 hours. The reactionmixture was quenched with water and the PH was adjusted to 6-7, and themixture was concentrated under reduced pressure. The residue waspurified with flash column chromatography using PE/EA=5/1 to afford theproduct 2-(4,4-dimethoxybutoxy)-5-nitropyridine (0.5 g, 1.95 mmol,30.8%) as a white solid. LC/MS: 224.9 [M+H−31]⁺.

Step 2: Preparation of 4-((5-nitropyridin-2-yl)oxy)butanal

A mixture of 2-(4,4-dimethoxybutoxy)-5-nitropyridine (500 mg, 1.95 mmol)in 2M H₂SO₄ (10 mL) was stirred at 70° C. for 1 hour. The reaction wasdiluted with NaHCO₃ and extracted with EA. The organic part wasconcentrated to afford the desired product (400 mg, 1.90 mmol, 97.5%) asa white solid. This product was directly used in the next step withoutany further purification. LC/MS: 211.0 [M+H]⁺.

Step 3: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-((4-((5-nitropyridin-2-yl)oxy)butyl)amino)cyclobutoxy)isoindoline-1,3-dione

To a solution of 4-((5-nitropyridin-2-yl)oxy)butanal (400 mg, 1.9 mmol)and5-((1r,3r)-3-aminocyclobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(651.7mg, 1.9 mmol) in dry THF (20 mL) was added NaBH(OAc)₃ (483.2 mg, 2.28mmol). The mixture was stirred at 25° C. for 48 hours. The mixture wasdiluted with DCM and washed with water for 3 times. The organic layerwas dried and concentrated. The residue was purified by flash columnchromatography eluted with DCM/MeOH (20:1) to afford the desired (360mg, 0.67 mmol, 35.3%) as a white solid. LC/MS: 538.3 [M+H]⁺.

Step 4: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(methyl(4-((5-nitropyridin-2-yl)oxy)butyl)amino)cyclobutoxy)isoindoline-1,3-dione

The above solid (360 mg, 0.67 mmol) and HCHO (1 mL) were dissolved inDCM (10 mL). Then NaBH(OAc)₃ (211.9 mg, 1.0 mmol) was added. The mixturewas stirred at room temperature for 2 hours. The reaction mixture waswashed with water and the organic phase was dried and concentrated. Theresidue was directly used without further purification. The product wasobtained as a white solid (356 mg, 0.65 mmol, 97.0%). LC/MS: 551.7[M+H]⁺

Step 5: Preparation of5-((1r,3r)-3-((4-((5-aminopyridin-2-yl)oxy)butyl)(methyl)amino)cyclobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

The above white solid (356 mg, 0.65 mmol) was dissolved in EtOH (20 mL).Then Fe (181 mg, 3.25 mmol), NH₄Cl (173.84 mg, 3.25 mmol), and water (2mL) were added. The mixture was stirred at 90° C. for 16 hours. Thereaction mixture was filtered, and the filtrate was concentrated toafford the desired product as a white solid without furtherpurification. (300 mg, 0.57 mmol, 88.5%). LC/MS: 522.1 [M+H]⁺.

Step 6: Preparation(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)butoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-8)

The above amine (60 mg, 0.12 mmol), phenyl carbonochloridate(18.87 mg,0.12 mmol), DMAP (1.4 mg, 0.012) and triethylamine (14.5 mg, 0.14 mmol)was stirred in MeCN (10 mL) at 25° C. for 2 hours. The reaction solutionwas concentrated and washed with water. Then the intermediate wasdissolved in MeCN and2-chloro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)benzonitrile (29.9 mg,0.12 mmol) was added. The mixture was stirred at 80° C. for 16 hours.The reaction was concentrated and purified by flash columnchromatography eluted with DCM/MeOH(15:1) to afford the desired product(20 mg, 0.025 mmol, 20.8%) as a yellow solid. LC/MS: 797.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO) δ 11.12 (s, 1H), 8.56 (s, 1H), 8.18 (d, J=2.6 Hz,1H), 7.85 (d, J=8.5 Hz, 1H), 7.77 (dd, J=8.9, 2.6 Hz, 1H), 7.67 (d,J=9.0 Hz, 1H), 7.34-7.14 (m, 3H), 7.00 (dd, J=9.1, 2.3 Hz, 1H), 6.73 (d,J=8.8 Hz, 1H), 5.17-4.95 (m, 2H), 4.50-4.41 (m, 1H), 4.37-4.15 (m, 3H),3.85 (d, J=13.7 Hz, 1H), 3.66 (d, J=12.1 Hz, 1H), 3.41-3.35 (m, 1H),3.33-3.28 (m, 2H), 2.96-2.78 (m, 2H), 2.73-2.53 (m, 3H), 2.46-2.16 (m,4H), 2.15-1.88 (m, 3H), 1.72 (s, 5H), 1.16 (d, J=6.6 Hz, 3H), 1.09 (d,J=6.5 Hz, 3H).

Synthesis of(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-14)

Step 1: Preparation of (1-(5-nitropyridin-2-yl)piperidin-4-yl)methanol

To a solution of 2-chloro-5-nitropyridine (5 g, 31.5 mmol) in EtOH (50mL) stirred at room temperature was added piperidin-4-ylmethanol (3.63g, 31.5 mmol). The reaction mixture was stirred at 80° C. for 2 hours.After the reaction completion, the mixture was cooled to roomtemperature and concentrated under vacuum. The residue was purified byflash column chromatography on silica gel (PE/EtOAc=3:1) to afford thedesired product (3.77 g, 50.4%) as a yellow solid. LC/MS: 238.0 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ=9.05 (d, J=2.8 Hz, 1H), 8.20 (dd, J=9.6, 2.8Hz, 1H), 6.60 (d, J=9.6 Hz, 1H), 4.59 (d, J=12.8 Hz, 2H), 3.57 (d, J=5.6Hz, 2H), 3.05 (t, J=12.8 Hz, 2H), 1.97-1.90 (m, 2H), 1.90-1.84 (m, 1H),1.37-1.24 (m, 2H).

Step 2: Preparation of 1-(5-nitropyridin-2-yl)piperidine-4-carbaldehyde

To a solution of (1-(5-nitropyridin-2-yl)piperidin-4-yl)methanol (3.77g, 15.9 mmol) in DCM (40 mL) stirred at room temperature was addedDess-Martin reagent (1.35 g, 31.8 mmol). The mixture was stirred at roomtemperature for 2 hours. The reaction was quenched by the addition ofsaturated sodium sulfite solution, the solid was filtered out, theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under vacuum. The crude product was used in next stepwithout further purification (3 g, 80.2%). LC/MS: 236.0 [M+H]⁺.

Step 3: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(5-nitropyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione

To a solution of Intermediate 2-1 (1.61 g, 4.25 mmol) in DCM/MeOH (13mL, 10:3) stirred at 15° C. was added AcONa (523 mg, 6.375 mmol). After30 minutes of stirring, AcOH (510 mg, 8.5 mmol) was added, then1-(5-nitropyridin-2-yl)piperidine-4-carbaldehyde (1 g, 4.25 mmol) wasadded. The mixture was stirred at 15° C. for 30 minutes, then NaCNBH₃(400 mg, 6.375 mmol) was added. The reaction mixture was stirred at 15°C. for 1 hour. LC/MS showed the reaction completed. The mixture wasquenched with 30 mL of water, extracted with DCM (30 mL×2). The combinedorganic layer was washed with brine, dried and concentrated under vacuumto give the crude product, which was purified by preparative TLC(DCM/MeOH=10:1) to afford the desired compound (500 mg, 20.9%) as ayellow solid. LC/MS: 561.9 [M+H]⁺.

Step 4: Preparation of5-(4-((1-(5-aminopyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(5-nitropyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione(500 mg, 0.89 mmol) in THF (5 mL) was added Pd/C (dry, 50 mg), and themixture was stirred under H₂ (0.4 MPa) at 60° C. for 12 hours. After thereaction completed, the mixture was filtered, and the filtrate wasconcentrated under vacuum to give a crude product, which was purified bypreparative TLC (DCM/MeOH=10:1) to afford the desired compound (160 mg,33.9%) as a yellow solid. LC/MS: 531.9 [M+H]⁺.

Step 5: Preparation of(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-14)

To a solution of5-(4-((1-(5-aminopyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(160 mg, 0.3 mmol) containing phenyl chloroformate (67 mg, 0.33 mmol),and TEA (33 mg, 0.33 mmol) in ACN (10 mL) was added DMAP (1.3 mg, 0.01mmol). The reaction mixture was stirred at r.t for 2 h and then quenchedby adding water (2 mL). Solvent was removed under vacuum and the residuewas dissolved in ACN (10 mL). Then2-chloro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)benzonitrile (75 mg, 0.3mmol) was added. The reaction mixture was stirred at 90° C. overnight.The mixture was concentrated under vacuum to give a crude product, andthe crude product was purified by preparative TLC (MeOH:DCM=1:10) togive the title compound (80 mg, 33%). LC/MS: 806.6 [M+H]⁺; ¹H NMR (400MHz, DMSO) δ 11.10 (s, 1H), 8.38 (s, 1H), 8.13 (s, 1H), 7.75-7.65 (m,2H), 7.58 (d, J=2.4 Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.17 (s, 1H),7.0 (d, J=2.4 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 5.08 (dd, J=12.0, 4.0 Hz,1H), 4.44 (br, 1H), 4.27 (br, 1H), 4.18 (d, J=3.6 HZ, 2H), 4.11 (br,1H), 3.84 (d, J=2.4 Hz, 1H), 3.62 (d, J=2.4 Hz, 1H), 3.4 (br s, 4H),3.29 (br, 2H), 3.17 (br, 2H), 2.91-2.83 (m, 2H), 2.80-2.71 (m, 2H),2.54-2.43 (m, 2H), 2.2 (br, 2H), 1.91 (br, 2H), 1.78 (d, J=2.4 Hz, 2H),1.23 (s, 2H), 1.15 (d, J=1.2 Hz, 3H), 1.08 (d, J=1.2 Hz, 3H).

Synthesis of(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-19)

Step 1: Preparation of2-(1-(5-nitropyridin-2-yl)piperidin-4-yl)ethan-1-ol

To a solution 2-chloro-5-nitropyridine (800 mg, 5.04 mmol) in EtOH (30mL) stirred under argon at room temperature was added 2-(piperidin-4-yl)ethanol (652 mg, 5.04 mmol) and K₂CO₃ (2092 mg, 15.14 mmol). Thereaction mixture was stirred at 80° C. for 12 hours. The crude productwas purified via silica gel column chromatography (DCM/MeOH=20:1) togive the title compound (1100 mg, 86%). LC/MS: 252.2 [M+H]⁺.

Step 2: Preparation of2-(1-(5-nitropyridin-2-yl)piperidin-4-yl)acetaldehyde

To a solution of 2-[1-(5-nitropyridin-2-yl) piperidin-4-yl] ethanol(1185 mg, 4.72 mmol) in DCM (10 mL) stirred under argon at roomtemperature was added Dess-Martin periodinane (4 g, 9.44 mmol). Thereaction mixture was stirred at room temperature for 5 hours. The crudeproduct was purified via silica gel column chromatography(DCM/MeOH=20:1) to give the title compound (450 mg, 38%). LC/MS: 250.2[M+H]⁺.

Step 3: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(1-(5-nitropyridin-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione

To a solution of Intermediate 2-1 (152 mg, 0.4 mmol) in DCM (10 mL) andMeOH (3 mL) stirred under argon at room temperature was added sodiumacetate trihydrate (49 mg, 0.6 mmol). The reaction mixture was stirredat room temperature for 30 minutes. To the reaction mixture was added2-(1-(5-nitropyridin-2-yl)piperidin-4-yl) acetaldehyde (100 mg, 0.4mmol) and acetic acid (48 mg, 0.8 mmol). The reaction mixture wasstirred at room temperature for 30 minutes. To the reaction mixture wasadded NaCNBH₃ (38 mg, 0.6 mmol). The reaction mixture was stirred atroom temperature for 1 hour. The residue was quenched with water (10 mL)and extracted with DCM (10 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated in vacuum. Thecrude product was purified via preparative TLC (DCM/MeOH=10:1) to givethe title compound (220 mg, 95%). LC/MS: 576.25 [M+H]⁺.

Step 4: Preparation of5-(4-(2-(1-(5-aminopyridin-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

A mixture of2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(1-(5-nitropyridin-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione(100 mg, 0.17 mmol), Pd/C (50 mg, 2.2 mmol) and THF (10 mL) was stirredunder hydrogen at room temperature for 2 hours. The crude product waspurified via preparative TLC (DCM/MeOH=10:1) to give the title compound(50 mg, 54%). LC/MS: 546.25 [M+H]⁺.

Step 5: Preparation of(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-19)

A mixture containing5-(4-(2-(1-(5-aminopyridin-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(50 mg, 0.09 mmol), TEA (22 mg, 0.22 mmol), DMAP (15 mg, 0.12 mmol),phenyl chloroformate (19 mg, 0.12 mmol) and acetonitrile (10 mL) wasstirred under hydrogen at room temperature for 2 hours. The residue wasquenched with water (10 mL) and concentrated under vacuum. To thereaction mixture was added Intermediate 1-1 (23 mg, 0.09 mmol), TEA (22mg, 0.22 mmol) and acetonitrile (10 mL). The reaction mixture wasstirred at 100° C. overnight. The crude product was first purified viapreparative TLC (DCM/MeOH=10:1) and further purified by reverse phasepreparative HPLC to give the title compound as a formic acid salt (10mg, 10%). LC/MS: 820.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 11.68 (s, 1H),11.11 (s, 1H), 8.78-8.52 (m, 1H), 8.20 (s, 1H), 7.83-7.59 (m, 3H), 7.48(s, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.17 (s, 1H), 7.01 (d, J=8.6 Hz, 1H),6.91-6.68 (m, 1H), 5.10 (dd, J=12.9, 5.1 Hz, 1H), 4.57-4.48 (m, 1H),4.30-4.15 (m, 4H), 4.00-3.88 (m, 1H), 3.68-3.60 (m, 1H), 3.58-3.47 (m,4H), 3.35-3.27 (m, 2H), 3.23-3.14 (m, 2H), 3.06-2.84 (m, 2H), 2.83-2.67(m, 2H), 2.65-2.55 (m, 2H), 2.20-1.97 (m, 3H), 1.80-1.67 (m, 3H),1.65-1.43 (m, 2H), 1.35-1.05 (m, 8H).

Synthesis of(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide(1-21)

Step 1: Preparation of (1-(5-nitropyrimidin-2-yl)piperidin-4-yl)methanol

To a solution of 2-chloro-5-nitropyrimidine (3 g, 18.8 mmol) in NMP (80mL) stirred in the air at room temperature was addedpiperidin-4-ylmethanol (2.16 g, 18.8 mmol), t-BuOK (6.3 g, 56.4 mmol).The reaction mixture was stirred at 90° C. for 16 hours. The mixture wastreated with water (80 mL) and extracted by DCM (150 mL×3). The organiclayers were combined and washed by brine, dried with MgSO₄. The solventwas removed under vacuum to give a crude product which was purified bysilica gel column chromatography and eluted with 0-10% MeOH in DCM togive the title compound (1.8 g, 40%). LC/MS: 239.1 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ 9.07 (s, 2H), 5.09-4.93 (m, 2H), 3.58 (d, J=6.0 Hz, 2H),3.05 (td, J=13.1, 2.4 Hz, 2H), 2.00-1.87 (m, 3H), 1.49 (s, 1H),1.35-1.23 (m, 2H).

Step 2: Preparation of1-(5-nitropyrimidin-2-yl)piperidine-4-carbaldehyde

To a solution of (1-(5-nitropyrimidin-2-yl)piperidin-4-yl)methanol (1 g,4.2 mmol) in DCM (20 mL) stirred at room temperature was addedDess-Martin reagent (2.6 g, 6.3 mmol). The reaction mixture was stirredat room temperature for 1 hour. The solvent was removed under vacuum.The crude product was purified by silica gel column chromatography andeluted with 0-20% EA in PE to give the title compound (800 mg, 80%).LC/MS: 237.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 9.75 (s, 1H), 9.08 (s,2H), 4.68 (dt, J=13.6, 4.3 Hz, 2H), 3.45 (ddd, J=13.6, 10.5, 3.2 Hz,2H), 2.65 (td, J=9.8, 4.8 Hz, 1H), 2.19-1.98 (m, 2H), 1.85-1.64 (m, 2H).

Step 3: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(5-nitropyrimidin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione

To a solution of 1-(5-nitropyrimidin-2-yl)piperidine-4-carbaldehyde (450mg, 1.9 mmol) and Intermediate 2-1 (722 mg, 1.9 mmol) in DCM (10 mL)stirred under nitrogen at room temperature was added magnesium sulphate(4.56 g, 38 mmol) and triethylamine (384 mg, 3.8 mmol). The reactionmixture was stirred at room temperature for 1 hour. Then NaBH(OAc)₃ (1g, 4.74 mmol) was added in portions. The reaction was stirred for 1hour. The solvent was removed in vacuum to give a crude product. Thecrude product was purified by silica gel column chromatography elutedwith 0-15% MeOH in DCM to give the title compound (900 mg, 84%). LC/MS:563.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 9.07 (s, 2H), 8.14 (s, 1H), 7.72(d, J=8.5 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.08 (dd, J=8.6, 2.2 Hz, 1H),5.32 (s, 2H), 5.01-4.92 (m, 3H), 3.45 (s, 3H), 3.10-3.01 (m, 2H),2.95-2.75 (m, 3H), 2.61 (s, 3H), 2.30 (d, J=6.8 Hz, 2H), 2.19-2.11 (m,1H), 2.02-1.88 (m, 3H), 1.28-1.16 (m, 2H).

Step 4: Preparation of5-(4-((1-(5-aminopyrimidin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(5-nitropyrimidin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione(900 mg, 1.6 mmol) in THF (100 mL) was added Pd/C (169 mg, 0.16 mmol)and the mixture was stirred under H₂ at room temperature for 4 hours.The mixture was filtered, and the solvent was removed in vacuum to givethe title compound (800 mg, 94%). LC/MS: 533.2 [M+H]⁺.

Step 5: Preparation of(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide(1-21)

To a solution containing5-(4-((1-(5-aminopyrimidin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(100 mg, 0.19 mmol), phenyl chloroformate (31.2 mg, 0.2 mmol), and TEA(20 mg, 0.2 mmol) in ACN (2 mL) was added DMAP (2.4 mg, 0.02 mmol). Thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was quenched by adding H₂O (2 mL). Solvent was removedunder vacuum and the residue was dissolved in ACN (10 mL). Then2-chloro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)benzonitrile (48 mg, 0.19mmol) was added. The reaction mixture was stirred at 90° C. overnight.Solvent was concentrated in vacuum to give a crude product. The crudeproduct was purified by preparative TLC eluted with MeOH:DCM=1:10 togive the title compound (70 mg, 45%). LC/MS: 808.2 [M+H]⁺; ¹H NMR (400MHz, DMSO) δ 11.10 (s, 1H), 8.42 (s, 1H), 8.36 (s, 2H), 7.68 (t, J=8.5Hz, 2H), 7.35 (s, 1H), 7.27 (d, J=8.6 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H),7.01 (dd, J=9.1, 2.1 Hz, 1H), 5.08 (dd, J=12.9, 5.3 Hz, 1H), 4.59 (d,J=13.0 Hz, 2H), 4.49-4.23 (m, 2H), 3.83 (d, J=13.5 Hz, 1H), 3.67 (d,J=12.7 Hz, 1H), 3.45 (s, 4H), 3.40-3.35 (m, 1H), 3.33-3.28 (m, 2H),2.93-2.81 (m, 3H), 2.68-2.52 (m, 5H), 2.20 (d, J=6.2 Hz, 2H), 2.07-1.97(m, 1H), 1.87-1.73 (m, 3H), 1.27-1.00 (m, 8H).

Synthesis of(2S,5R)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide(1-22)

This compound was prepared using the same method as described for thepreparation of 1-21. LC/MS: 808.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 11.10(s, 1H), 8.43 (s, 1H) 8.36 (s, 2H), 7.68 (t, J=8.7 Hz, 2H), 7.35 (s,1H), 7.27 (d, J=8.6 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 7.01 (dd, J=9.2,2.1 Hz, 1H), 5.08 (dd, J=12.8, 5.3 Hz, 1H), 4.59 (d, J=12.9 Hz, 2H),4.49-4.23 (m, 2H), 3.83 (d, J=13.2 Hz, 1H), 3.67 (d, J=12.6 Hz, 1H),3.52-3.36 (m, 5H), 3.32-3.26 (m, 3H), 2.86 (t, J=12.9 Hz, 3H), 2.65-2.54(m, 4H), 2.20 (s, 2H), 2.03-1.98 (m, 1H), 1.86-1.73 (m, 3H), 1.27-1.05(m, 8H).

Synthesis of(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-26)

This compound was prepared using the same method as described for thepreparation of 1-14 except that Intermediate 1-3 was used in the finalstep of urea formation. LC/MS: 803.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ11.10 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.55-7.65 (m, 1H), 7.61-7.55(m, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.35 (s, 1H), 7.30-7.23 (m, 1H),6.83-6.74 (m, 1H), 6.63-6.57 (m, 1H), 6.55-6.50 (m, 1H), 5.15-5.05 (m,1H), 4.50-4.43 (m, 1H), 4.35-4.23 (m, 1H), 4.22-4.15 (m, 2H), 3.90 (s,3H), 3.86 (m, 1H), 3.65-3.53 (m, 2H), 3.50-3.42 (m, 3H), 3.39-3.35 (m,1H), 3.16-3.05 (m, 1H), 3.00-2.80 (m, 2H), 2.90-2.53 (m, 7H), 2.30-2.10(m, 2H), 2.08-1.98 (m, 1H), 1.90-1.75 (m, 3H), 1.23 (br s, 2H), 1.17 (d,J=6.6 Hz, 3H), 1.08 (d, J=6.5 Hz, 3H).

Synthesis of(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide(1-29)

This compound was prepared using the same method as described for thepreparation of 1-14. LC/MS: 838.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 11.10(s, 1H), 8.31 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H),7.36 (s, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.20 (dd, J=13.6, 7.5 Hz, 1H),6.89 (dd, J=12.1, 8.2 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 6.53 (s, 1H),5.09 (dd, J=12.9, 5.3 Hz, 1H), 4.43 (br, 1H), 4.27 (br, 1H), 3.90 (s,3H), 3.82 (d, J=13.1 Hz, 1H), 3.60 (d, J=12.0 Hz, 1H), 3.46 (s, 4H),3.37 (d, J=13.7 Hz, 2H), 3.30 (m, 3H), 2.88 (d, J=11.9 Hz, 1H),2.71-2.52 (m, 7H), 2.25 (d, J=5.2 Hz, 2H), 2.07-1.97 (m, 1H), 1.83 (d,J=11.2 Hz, 2H), 1.69 (br s, 1H), 1.36-1.23 (m, 2H), 1.19 (d, J=6.6 Hz,3H), 1.09 (d, J=6.4 Hz, 3H).

Synthesis of(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-30)

This compound was prepared using the same method as described for thesynthesis of 1-14. LC/MS: 841.3 [M+H]⁺; 1H NMR (400 MHz, DMSO) δ 11.10(s, 1H), 8.46-8.39 (m, 1H), 8.14 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.69(d, J=8.2 Hz, 1H), 7.63-7.57 (m, 2H), 7.36 (s, 1H), 7.31-7.26 (m, 2H),6.82-6.76 (m, 1H), 5.12-5.06 (m, 1H), 4.52-4.30 (m, 3H), 4.19 (d, J=11.4Hz, 3H), 3.87 (d, J=14.0 Hz, 1H), 3.73 (d, J=11.7 Hz, 1H), 3.46 (s, 2H),3.42-3.36 (m, 2H), 3.20-3.02 (m, 3H), 2.96-2.83 (m, 2H), 2.77-2.73 (m,1H), 2.70-2.54 (m, 2H), 2.36-2.32 (m, 1H), 2.21 (s, 2H), 2.08-1.98 (m,2H), 1.83-1.76 (m, 2H), 1.25-1.10 (m, 8H).

Synthesis of(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide(1-31)

This compound was prepared using the same method as described for thepreparation of 1-14 except that Intermediate 1-4 was used in the finalstep of urea formation. LC/MS: 842.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ11.10 (s, 1H), 8.52 (s, 1H), 8.38 (s, 2H), 7.85 (d, J=8.7 Hz, 1H),7.75-7.65 (m, 1H), 7.40-7.21 (m, 4H), 5.14-5.06 (m, 1H), 4.65-4.54 (m,2H), 4.53-4.30 (m, 3H), 3.91-3.83 (m, 1H), 3.77-3.71 (m, 1H), 3.54-3.43(m, 6H), 3.22-3.03 (m, 2H), 2.92-2.80 (m, 3H), 2.72-2.57 (m, 3H),2.25-2.15 (m, 2H), 2.07-2.00 (m, 1H), 1.90-1.77 (m, 3H), 1.28-1.15 (m,8H).

Synthesis of(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-43)

Step 1: Preparation of(S)-3-(5-(4-((1-(5-nitropyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of Intermediate 2-2 (617 mg, 1.27 mmol) in DCM/MeOH (15mL, 10:3) stirred at 15° C. was added AcONa (156 mg, 1.9 mmol). After 30minutes, AcOH (152 mg, 2.54 mmol) was added, then1-(5-nitropyridin-2-yl)piperidine-4-carbaldehyde (300 mg, 1.27 mmol) wasadded. The mixture was stirred at 15° C. for 30 minutes before NaCNBH₃(119.7 mg, 1.9 mmol) was added. The reaction mixture was stirred at 15°C. for 1 hour. LC/MS showed the reaction completed. The mixture wasquenched with the addition of 30 mL of water, extracted with DCM (30mL×2), and the combined organic layer was washed with brine, dried andconcentrated under vacuum to give a crude product, which was purified bysilica gel column chromatography (DCM/MeOH=10:1) to afford the desiredcompound (150 mg, 21.5%) as a yellow solid. LC/MS: 548.6 [M+H].

Step 2: Preparation of(S)-3-(5-(4-((1-(5-aminopyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a stirred mixture of(S)-3-(5-(4-((1-(5-nitropyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(260 mg, 0.47 mmol) in EtOH (10 mL) and H₂O (10 mL) was added Fe (183mg, 3.32 mmol) and NH₄Cl (125 mg, 2.35 mmol), and the mixture wasstirred at 70° C. for 2 hours. After the reaction completed, the solidwas filtered, and the filtrate was concentrated under vacuum to give acrude product, which was purified by flash column chromatography(DCM/MeOH=10:1) to afford the desired compound (50 mg, 20.3%) as a brownsolid. LC/MS: 518.4 [M+H]⁺.

Step 3: Preparation of(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-43)

To a solution containing(S)-3-(5-(4-((1-(5-aminopyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(40 mg, 0.08 mmol), phenyl chloroformate (14.9 mg, 0.09 mmol), and TEA(8.9 mg, 0.09 mmol) in ACN (10 mL) was added DMAP (1.3 mg, 0.01 mmol).The reaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was quenched by adding H₂O (2 mL). Solvents wereremoved under reduced pressure and the residue was dissolved in ACN (10mL). Then4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-2-(trifluoromethyl)benzonitrile(Intermediate 1-4, 25.52 mg, 0.08 mmol) was added. The reaction mixturewas stirred at 90° C. overnight. The mixture was concentrated in vacuumand the crude residue was purified by preparative TLC (MeOH/DCM=1:10) togive the title compound (9.2 mg, 13.6%). LC/MS: 827.6 [M+H]⁺; HRMS:827.4022; ¹H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 8.52 (br s, 1H), 8.18(s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.74 (br, 1H), 7.62 (d, J=8.5 Hz, 1H),7.34-7.25 (m, 2H), 7.23-7.14 (m, 2H), 7.00 (br, 1H), 5.08 (dd, J=13.4,4.9 Hz, 1H), 4.46 (s, 1H), 4.37 (d, J=16.8 Hz, 2H), 4.28-4.17 (m, 3H),4.06-3.99 (m, 1H), 3.86 (d, J=13.4 Hz, 1H), 3.75 (d, J=13.6 Hz, 2H),3.40-3.38 (m, 1H), 3.37-3.34 (m, 1H), 3.24-3.11 (m, 4H), 2.94-2.86 (m,2H), 2.69-2.62 (m, 2H), 2.57 (d, J=14.5 Hz, 1H), 2.43-2.38 (m, 1H),2.37-2.32 (m, 1H), 2.13 (br, 2H), 2.00-1.95 (m, 1H), 1.85 (br d, J=11.0Hz, 3H), 1.33-1.04 (m, 8H).

Synthesis of(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-33)

This compound was prepared using the same method as described for thesynthesis of 1-43. LC/MS: 789.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.97(s, 1H), 8.37 (s, 1H), 8.15-8.10 (m, 1H), 7.59 (d, J=9.1 Hz, 1H), 7.53(d, J=8.5 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.12-7.04 (m, 2H), 6.78 (d,J=9.1 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H), 6.54 (s, 1H), 5.06 (dd, J=13.3,5.0 Hz, 1H), 4.45 (brs, 1H), 4.37-4.16 (m, 5H), 3.92-3.80 (s and d, 4H),3.61 (d, J=12.8 Hz, 1H), 3.33-3.22 (m, 8H), 2.93-2.86 (m, 2H), 2.74 (t,J=11.8 Hz, 2H), 2.60 (d, J=16.6 Hz, 1H), 2.44-2.31 (m, 2H), 2.21 (d,J=6.4 Hz, 2H), 2.00-1.94 (m, 1H), 1.79 (d, J=10.7 Hz, 3H), 1.27-1.01 (m,8H).

Synthesis of(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide(1-44)

This compound was prepared using the same method as described for thesynthesis of 1-43. LC/MS: 792.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.97(s, 1H), 8.38 (s, 1H), 8.13 (d, J=2.6 Hz, 1H), 7.67 (d, J=8.9 Hz, 1H),7.59 (dd, J=9.0, 2.6 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.18 (d, J=1.9 Hz,1H), 7.14-7.04 (m, 2H), 7.04-6.96 (m, 1H), 6.77 (d, J=9.2 Hz, 1H), 5.06(dd, J=13.4, 5.1 Hz, 1H), 4.45 (brs, 1H), 4.39-4.12 (m, 5H), 3.85 (d,J=14.0 Hz, 1H), 3.66 (d, J=12.7 Hz, 1H), 3.34-3.22 (m, 8H), 2.96-2.85(m, 2H), 2.73 (t, J=11.7 Hz, 2H), 2.67-2.54 (m, 1H), 2.43-2.30 (m, 2H),2.21 (d, J=6.5 Hz, 2H), 2.01-1.94 (m, 1H), 1.79 (d, J=10.3 Hz, 3H),1.29-1.10 (m, 8H).

Synthesis of(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide(1-48)

This compound was prepared using the same method as described in thesynthesis of 1-14. LC/MS: 819.5 [M+H]⁺; 1H NMR (400 MHz, DMSO) δ 11.09(s, 1H), 8.57 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.49-7.32 (m, 3H),7.31-7.22 (d, J=7.9 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 6.94 (t, J=9.4 Hz,1H), 6.59 (d, J=8.0 Hz, 1H), 6.53 (s, 1H), 5.07 (dd, J=12.8, 5.2 Hz,1H), 4.46 (br m, 1H), 4.28 (br, 1H), 3.89 (s, 3H), 3.85 (d, J=12.5 Hz,1H), 3.59 (d, J=12.5 Hz, 1H), 3.49-3.37 (m, 6H), 3.31-3.20 (m, 4H),2.93-2.83 (m, 1H), 2.67-2.54 (m, 6H), 2.28-2.18 (m, 2H), 2.07-1.95 (m,1H), 1.86-1.75 (m, 2H), 1.70-1.61 (m, 1H), 1.41-1.21 (m, 2H), 1.17 (d,J=6.5 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H).

Synthesis of(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide(1-49)

This compound was prepared using the same method as described in thesynthesis of 1-43. LC/MS: 827.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 10.96(s, 1H), 8.47 (brs, 1H), 8.37 (d, J=3.2 Hz, 2H), 7.85 (d, J=8.9 Hz, 1H),7.54 (d, J=8.3 Hz, 1H), 7.32-7.26 (m, 2H), 7.09 (s, 2H), 5.06 (dd,J=13.3, 5.0 Hz, 1H), 4.59 (d, J=12.8 Hz, 2H), 4.46 (brs, 1H), 4.35 (d,J=17.1 Hz, 2H), 4.26-4.19 (m, 1H), 3.96-3.81 (m, 1H), 3.74 (d, J=12.1Hz, 1H), 3.44-3.36 (m, 2H), 3.32-3.27 (m, 6H), 2.97-2.80 (m, 3H), 2.59(d, J=16.0 Hz, 1H), 2.46-2.30 (m, 3H), 2.21 (brs, 2H), 2.00-1.94 (m,1H), 1.90-1.74 (m, 3H), 1.33-1.23 (m, 2H), 1.18 (d, J=6.6 Hz, 3H), 1.11(d, J=6.5 Hz, 3H).

Synthesis of(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide(1-51)

This compound was prepared using the same method as described for thepreparation of 1-43. LC/MS: 793.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ=10.97(s, 1H), 8.44 (s, 1H), 8.36 (s, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.54 (d,J=7.6 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 7.1 (s, 2H), 7.01 (dd, J=8.8, 2.0Hz, 1H), 5.06 (dd, J=9.2, 4.8 Hz, 1H), 4.59 (d, J=11.2 Hz, 2H), 4.43 (brs, 1H), 4.37-4.19 (m, 3H), 3.83 (d, J=13.2 Hz, 1H), 3.67 (d, J=12.4 Hz,1H), 3.35-3.25 (m, 7H), 3.13-3.06 (m, 1H), 2.96-2.83 (m, 3H), 2.65-2.53(m, 2H), 2.44-2.31 (m, 2H), 2.23-2.17 (m, 2H), 2.03-1.93 (m, 1H), 1.8(d, J=11.6 Hz, 2H), 1.48 (m, 1H), 1.35-1.24 (m, 2H), 1.17 (d, J=6.4 Hz,3H), 1.09 (d, J=6.4 Hz, 3H).

Synthesis of(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide(1-52)

This compound was prepared using the same method as described for thesynthesis of 1-43. LC/MS: 789.7 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ=10.97(s, 1H), 8.46 (s, 1H), 8.36 (s, 2H), 7.55 (d, J=7.6 Hz, 1H), 7.44 (d,J=8.4 Hz, 1H), 7.10 (s, 2H), 6.61 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 5.06(d, J=13.2 Hz, 1H), 4.59 (d, J=12.4 Hz, 2H), 4.44 (s, 1H), 4.36-4.18 (m,3H), 3.90 (s, 3H), 3.85 (d, J=13.6 Hz, 1H), 3.62 (d, J=12.4 Hz, 1H),3.50-3.20 (m, 8H), 2.92-2.80 (m, 3H), 2.60 (m, 4H), 2.44-2.31 (m, 2H),1.97 (m, 2H), 1.81 (d, J=11.2 Hz, 2H), 1.29-1.09 (m, 8H).

Synthesis of(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide(1-53)

This compound was prepared using the same method as described for thesynthesis of 1-43. LC/MS: 805.4[M+1]⁺; ¹H NMR (400 MHz, DMSO) δ=10.96(s, 1H), 8.56 (s, 1H), 7.53 (d, J=8.7, 1H), 7.43 (d, J=8.8, 1H), 7.38(d, J=15.3, 1H), 7.16 (d, J=8.2, 1H), 7.12-7.06 (s, 2H), 6.98-6.90 (m,1H), 6.59 (d, J=8.9, 1H), 6.52 (s, 1H), 5.08-5.03 (m, 1H), 4.49-4.43 (m,1H), 4.37-4.31 (m, 2H), 4.24-4.18 (m, 1H), 3.94-3.81 (m, 4H), 3.60 (d,J=12.2, 1H), 3.50-3.00 (m. 10H)), 2.93-2.87 (m, 2H), 2.69-2.55 (m, 3H),2.43-2.20 (m, 4H), 1.96-1.66 (m, 4H), 1.40-1.22 (m, 2H), 1.17 (d, J=6.6,3H), 1.06 (d, J=6.5, 3H).

Synthesis of(2R,5S)-4-(8-cyanoquinolin-5-yl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide(2-18)

Step 1: Preparation of(S)-3-(5-(4-((1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution containing1-(2,5-difluoro-4-nitrophenyl)piperidine-4-carbaldehyde (90 mg, 0.33mmol) and Intermediate 2-2 (162 mg, 0.33 mmol) in DCM (5 mL) stirredunder nitrogen at room temperature was added magnesium sulphate (800 mg,6.67 mmol) and triethylamine (67 mg, 0.67 mmol). The reaction mixturewas stirred at room temperature for 1 hour. Then NaBH(OAc)₃ (177 mg,0.83 mmol) was added in portions. The reaction was stirred for 1 hour.The solvent was removed in vacuum to give a crude product which waspurified by silica gel column chromatography (0-15% MeOH in DCM) to givethe title compound (200 mg, 100%). LC/MS: 582.6 [M+H]⁺; ¹H NMR (400 MHz,DMSO) δ 10.96 (s, 1H), 7.97 (dd, J=13.8, 7.4 Hz, 1H), 7.53 (d, J=8.7 Hz,1H), 7.14-6.99 (m, 3H), 5.06 (dd, J=13.2, 5.1 Hz, 1H), 4.39-4.19 (m,2H), 3.78 (d, J=12.6 Hz, 2H), 3.31-3.25 (m, 6H), 3.05-2.94 (m, 2H),2.93-2.85 (m, 1H), 2.65-2.54 (m, 2H), 2.42-2.30 (m, 2H), 2.23 (d, J=6.5Hz, 2H), 1.95 (dd, J=15.1, 9.9 Hz, 1H), 1.84 (d, J=10.2 Hz, 3H),1.31-1.14 (m, 2H).

Step 2: Preparation of(S)-3-(5-(4-((1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of(S)-3-(5-(4-((1-(2,5-difluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.34 mmol) in THF (20 mL) was added Pd/C (35 mg) and stirredunder H₂ at room temperature for 4 hours. The mixture was filtered, andthe solvent was removed in vacuum to give the title compound (140 mg,74%). LC/MS: 552.7 [M+H]⁺.

Step 3: Preparation of(2R,5S)-4-(8-cyanoquinolin-5-yl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide(2-18)

To a solution containing(S)-3-(5-(4-((1-(4-amino-2,5-difluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(140 mg, 0.25 mmol), phenyl chloroformate (58 mg, 0.37 mmol), and TEA(37 mg, 0.37 mmol) in ACN (2 mL) was added DMAP (3.6 mg, 0.03 mmol). Thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was quenched by adding H₂O (2 mL). Solvent was removedunder vacuum and the residue was dissolved in ACN (10 mL). Then5-((2S,5R)-2,5-dimethylpiperazin-1-yl)quinoline-8-carbonitrile(Intermediate 1-5, 67 mg, 0.25 mmol) was added. The reaction mixture wasstirred at 90° C. overnight. The mixture was concentrated in vacuum andthe residue was purified by preparative TLC (MeOH:DCM=1:10) to give thetitle compound (31 mg, 15%). LC/MS: 844.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO)δ 10.95 (s, 1H), 9.06 (dd, J=4.1, 1.3 Hz, 1H), 8.69 (d, J=8.6 Hz, 1H),8.37-8.17 (m, 2H), 7.70 (dd, J=8.5, 4.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H),7.28-7.15 (m, 2H), 7.12-7.03 (m, 2H), 6.89 (dd, J=12.2, 8.2 Hz, 1H),5.06 (dd, J=13.2, 5.0 Hz, 1H), 4.55 (br, 1H), 4.36 (d, J=16.5 Hz, 1H),4.22 (d, J=16.5 Hz, 1H), 3.91 (m, 1H), 3.85 (br s, 2H), 3.75 (dd,J=12.1, 3.5 Hz, 1H), 3.36 (m, 3H), 3.31-3.22 (m, 3H), 2.97-2.85 (m, 2H),2.74-2.60 (m, 3H), 2.58 (s, 3H), 2.43-2.32 (m, 2H), 2.25 (d, J=5.9 Hz,2H), 2.02-1.93 (m, 1H), 1.83 (d, J=11.6 Hz, 2H), 1.70 (br, 1H), 1.35 (d,J=6.6 Hz, 3H), 1.30 (d, J=10.2 Hz, 2H), 0.90 (d, J=6.4 Hz, 3H).

Synthesis of(2R,5S)-4-(8-cyanoquinolin-5-yl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide(2-17)

This compound was prepared using the same method as for the preparationof 1-29 except Intermediate 1-5 was used in the final step of ureaformation. LC/MS: 858.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 11.08 (s, 1H),9.06 (d, J=3.2 Hz, 1H), 8.69 (d, J=8.3 Hz, 1H), 8.37-8.18 (m, 2H), 7.70(dd, J=8.4, 3.3 Hz, 2H), 7.35 (s, 1H), 7.30-7.16 (m, 3H), 6.89 (dd,J=12.1, 8.2 Hz, 1H), 5.13-5.03 (m, 1H), 4.56 (m, 1H), 3.95-3.80 (m, 3H),3.75 (d, J=8.5 Hz, 1H), 3.46 (br s, 4H), 3.34 (m, 3H), 2.96-2.85 (dd,J=18.1, 8.5 Hz, 2H), 2.75-2.61 (m, 3H), 2.60-2.53 (m, 4H), 2.30-2.19 (m,2H), 2.06-1.99 (m, 1H), 1.83 (d, J=11.8 Hz, 2H), 1.70 (brs, 1H), 1.35(d, J=6.6 Hz, 3H), 1.30 (d, J=11.1 Hz, 2H), 0.94-0.86 (m, 3H).

Synthesis of(2R,5S)-4-(8-cyanoquinolin-5-yl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide(2-12)

This compound was prepared using the same method in the preparation of1-29. LC/MS: 840.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.06(dd, J=4.2, 1.5 Hz, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.59 (s, 1H), 8.28-8.23(m, 1H), 7.70 (dd, J=8.6, 4.2 Hz, 2H), 7.48-7.15 (m, 5H), 6.99-6.92 (m,1H), 5.11-5.06 (m, 1H), 4.58 (br, 1H), 3.95-3.71 (m, 5H), 3.46 (br s,4H), 3.33-3.21 (m, 4H), 2.95-2.87 (m, 2H), 2.69-2.56 (m, 5H), 2.35-2.24(m, 2H), 2.13-1.93 (m, 1H), 1.92-1.76 (m, 2H), 1.74-1.58 (m, 1H),1.36-1.23 (m, 5H), 0.88 (d, J=6.5 Hz, 3H).

Testing of Compounds for AR Degradation Activity

LNCAP, VCAP and 22Rv1 cells were plated in 24-well plates at 1.5×10E5cells/well in the RPMI growth medium containing 10% FBS and 1%Penicillin Streptomycin, and then incubated at 37° C. overnight. Thefollowing day, the test compound was administered to the cells by using1000× compound stock solution prepared in DMSO at variousconcentrations. After administration of the compound, the cells werethen incubated at 37° C. for 24 hours. Upon completion, the cells werewashed with PBS and protein was collected in Laemmli sample buffer (1×;VWR International). Proteins in cell lysate were separated by SDS-PAGEand transferred to Odyssey nitrocellulose membranes (Licor) with iblot®dry blotting transfer system (ThermoFisher). Nonspecific binding wasblocked by incubating membranes with Intercept Blocking Buffer (Licor)for 1 hour at room temperature with gentle shaking. The membranes werethen incubated overnight at 4° C. with Primary antibodies rabbit anti-AR(1:1,000, Cell Signaling, 5153) and mouse anti-GAPDH (1:5,000, SantaCruz Biotechnology, sc-47724) diluted in Intercept Blocking Buffercontaining 0.1% Tween 20. After washing 3 times with TBS-T, themembranes were incubated with IRDye® 800CW goat anti-mouse IgG(1:20,000, Licor) or IRDye® 800CW goat anti-rabbit IgG (1:20,000, Licor)for 1 hour. After TBS-T washes, membranes were rinsed in TBS and scannedon Odyssey® CLx Imaging System (Licor). The bands were quantified usingImage Studio™ Software (Licor).

Tables 5 and 6 summarize the androgen receptor (AR) degradative activityof exemplary compounds in LNCAP, VCAP and 22Rv1 cell lines 24 hoursafter administration. DC50: compound concentration needed for 50% targetprotein degradation.

TABLE 5 AR degradative activity of compounds from cellular assays (A:≤10 nM; B: >100 nM, C: >10 nM and ≤100 nM) LNCAP VCAP 22RV1 Compound(DC50, nM) (DC50, nM) (DC50, nM) 1-20 A A A 1-13 A A N/A 1-21 A A N/A1-31 A A N/A 1-14 A A N/A 1-26 A A N/A 1-22 B B N/A 1-30 A A N/A 1-29 AA N/A 1-27 A A N/A 1-28 A A N/A 1-43 A A A 1-19 A N/A N/A 1-44 A N/A N/A1-33 A N/A N/A 1-45 A N/A N/A 1-46 A N/A N/A 1-47 A N/A N/A 1-48 A A A1-53 A A A 1-49 A N/A N/A 1-50 A N/A N/A 1-52 A N/A N/A 1-41 A N/A N/A1-39 A N/A N/A 1-54 A N/A N/A 1-51 A N/A N/A 1-23 A N/A N/A 1-25 A N/AN/A 1-11 A N/A N/A 1-9 A N/A N/A 1-12 C N/A N/A 1-10 C N/A N/A 1-8 A N/AN/A 1-55 A N/A N/A 1-56 A N/A N/A

TABLE 6 AR degradative activity of compounds from cellular assay (A: ≤10nM; B: >100 nM, C: >10 nM and ≤100 nM) LNCAP VCAP 22RV1 Compound (DC50,nM) (DC50, nM) (DC50, nM) 2-18 B N/A N/A 2-17 B N/A N/A 2-12 B N/A N/A2-21 B N/A N/A 2-10 B N/A N/A 2-11 B N/A N/A 2-9 B N/A N/A 2-8 B N/A N/A2-22 B N/A N/A 2-24 B N/A N/A 2-15 B N/A N/A 2-23 B N/A N/A 2-16 B N/AN/A 2-13 B N/A N/A 2-14 A N/A N/A

The many features and advantages of the present disclosure are apparentfrom the detailed specification, and thus it is intended by the appendedclaims to cover all such features and advantages of the presentdisclosure that fall within the true spirit and scope of the presentdisclosure. Further, since numerous modifications and variations willreadily occur to those skilled in the art, it is not desired to limitthe present disclosure to the exact construction and operationillustrated and described and accordingly, all suitable modificationsand equivalents may be resorted to, falling within the scope of thepresent disclosure.

Moreover, those skilled in the art will appreciate that the conceptionupon which this disclosure is based may readily be used as a basis fordesigning other structures, methods, and systems for carrying out theseveral purposes of the present disclosure. Accordingly, the claims arenot to be considered as limited by the foregoing description orexamples.

What is claimed is:
 1. A compound of Formula 1 or a pharmaceuticallyacceptable salt thereof:

wherein: X₁ is CR₁ or N; X₂ is CR₂ or N; X₃ is CR₃ or N; X₄ is CR₄ or N;each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halogen, C₁-C₃alkoxy, and C₁-C₃haloalkyl, each of which is substitutedwith 0, 1, 2, or 3 Rs; each R₅ is independently selected from halogen,hydroxyl, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN,each of which is substituted with 0, 1, 2, or 3 Rs; each R₆ isindependently selected from hydrogen, C₁-C₃alkyl, and C₁-C₃haloalkyl,each of which is substituted with 0, 1, 2, or 3 Rs; each R₇ isindependently selected from halogen, hydroxyl, C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃haloalkyl, —N(R₉)₂, and —CN, each of which is substituted with 0,1, 2, or 3 Rs; each R₈ is independently selected from hydrogen,hydroxyl, C₁-C₃alkyl, and C₁-C₃haloalkyl, each of which is substitutedwith 0, 1, 2, or 3 Rs, or two R₈ groups are taken together to form anoxo; each R₉ is independently selected from hydrogen, C₁-C₃alkyl,—C(═O)—(C₁-C₃alkyl), —C(═O)—O—(C₁-C₃alkyl), and —C(═O)—NH—(C₁-C₃alkyl),each of which is substituted with 0, 1, 2, or 3 Rs, or two R₉ groups aretaken together to form a 3- to 6-membered heterocycle or heteroaryl;each Rs is independently selected from halogen, hydroxyl, C₁-C₃alkyl,C₁i-C₃alkoxy, C₁-C₃haloalkyl, —N(R₉)₂, and —CN; L is a linker of 1 to 16carbon atoms in length, wherein one or more carbon atoms are optionallyreplaced by C(═O), O, N(R₉), S, C₂-alkenyl, C₂-alkynyl, cycloalkyl,aryl, heterocycle, or heteroaryl, wherein the R₉, C₂-alkenyl,cycloalkyl, aryl, heterocycle, and heteroaryl are each independentlysubstituted with 0, 1, 2, or 3 Rs; m is 0, 1, 2, or 3; and n is 0, 1, 2,or 3, wherein each hydrogen atom is independently and optionallyreplaced by a deuterium atom.
 2. The compound according to claim 1,wherein X₁ is CR₁, X₂ is CR₂, X₃ is CR₃, and X₄ is CR₄.
 3. The compoundaccording to claim 2, wherein R₁, R₂, R₃, and R₄ are each independentlyselected from H and F.
 4. The compound according to claim 1, whereineach R₅ is independently selected from halogen, C₁-C₃alkoxy, andC₁-C₃haloalkyl.
 5. The compound according to claim 1, wherein each R₆ isindependently selected from H and C₁-C₃alkyl.
 6. The compound accordingto claim 1, wherein each R₈ is hydrogen or two R₈ groups are takentogether to form an oxo.
 7. The compound according to claim 1, wherein Lis a linker of 1 to 6 carbon atoms in length, wherein one or more carbonatoms are optionally replaced by C(═O), O, N(R₉), S, C₂-alkenyl,C₂-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein theR₉, C₂-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are eachindependently substituted with 0, 1, 2, or 3 Rs.
 8. The compoundaccording to claim 1, wherein L is selected from:


9. The compound according to claim 1, wherein the compound is chosenfrom:(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)oxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propoxy)propoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-₁-yl)ethoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5yl)piperazin-1-yl)butoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl)oxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)butoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(ethyl)amino)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((((1r,3)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)pipendin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((((1s,3s)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2-methylpiperazine-1-carboxamide;(3S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-3-methylpiperazine-1-carboxamide;(3R)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-3-methylpiperazine-1-carboxamide;4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(2-(4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pipendin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pipendin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2S,5R)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pipendin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pipendin-1-yl)-2-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pipendin-1-yl)-2,6-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pipendin-1-yl)-2-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(6-(4-((4-(2-(2,6-dioxopipendin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pipendin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(2-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-fluoro-5-methoxyphenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-fluoro-5-methoxyphenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-fluoro-5-methoxyphenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;(2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;or a pharmaceutically salt thereof, wherein each hydrogen atom isindependently and optionally replaced by a deuterium atom.
 10. Apharmaceutical composition comprising at least one compound orpharmaceutically acceptable salt thereof according to claim 1 and apharmaceutically acceptable carrier.